en-usBasic ScienceThe goal of this collection is to highlight <i> Kidney360âs</i> ever-expanding scientifically rigorous and impactful basic science research articles. The Kidney360 editorial team is honored to publish and disseminate basic science research of this caliber to help the scientific community increase the understanding of disease processes. As new articles in basic science are published, they will automatically be added to this collection.<p></p>Thu, 28 Mar 2024 09:29:28 GMThttp://cct.highwire.org/feeds/asn/basic-science.rss- Zinc Deficiency: Potential Hidden Driver of the Detrimental Cycle of Chronic Kidney Disease and HypertensionGlobally, over 103 million individuals are afflicted by chronic kidney disease (CKD), a silent killer claiming the lives of 1.2 million people annually. CKD is characterized by 5 progressive stages, in which dialysis and kidney transplant are life-saving routes for patients with end-stage kidney failure. While kidney damage impairs kidney function and derails blood pressure regulation, uncontrolled hypertension accelerates the development and progression of CKD. Zinc (Zn) deficiency has emerged as a potential hidden driver within this detrimental cycle of CKD and hypertension. This review article will 1) highlight mechanisms of Zn procurement and trafficking, 2) provide evidence that urinary Zn wasting can fuel Zn deficiency in CKD, 3) discuss how Zn deficiency can accelerate the progression of hypertension and kidney damage in CKD, and 4) consider Zn supplementation as an exit strategy with the potential to rectify the course of hypertension and CKD progression.clintoria.williams@wright.edu10.34067/KID.0007812021Sun, 18 Dec 2022 09:38:34 GMT-08:00Zinc Deficiency: Potential Hidden Driver of the Detrimental Cycle of Chronic Kidney Disease and HypertensionGlobally, over 103 million individuals are afflicted by chronic kidney disease (CKD), a silent killer claiming the lives of 1.2 million people annually. CKD is characterized by 5 progressive stages, in which dialysis and kidney transplant are life-saving routes for patients with end-stage kidney failure. While kidney damage impairs kidney function and derails blood pressure regulation, uncontrolled hypertension accelerates the development and progression of CKD. Zinc (Zn) deficiency has emerged as a potential hidden driver within this detrimental cycle of CKD and hypertension. This review article will 1) highlight mechanisms of Zn procurement and trafficking, 2) provide evidence that urinary Zn wasting can fuel Zn deficiency in CKD, 3) discuss how Zn deficiency can accelerate the progression of hypertension and kidney damage in CKD, and 4) consider Zn supplementation as an exit strategy with the potential to rectify the course of hypertension and CKD progression.Ume, Adaku C.Wenegieme, Tara-YesomiAdams, Danielle N.Adesina, Sherry E.Williams, Clintoria R.2022-12-18T21:38:34-08:00doi:10.34067/KID.0007812021hwp:resource-id:kidney360;KID.0007812021v1American Society of NephrologyCopyright © 2022 American Society of NephrologyKidney360Zinc, Zinc wasting, Kidney damage, Zinc deficiency, Hypertension, Chronic Kidney Disease, Zinc supplementationBasic Science for CliniciansBasic Science for Cliniciansother202210.34067/KID.00078120212641-76502641-76502022-12-18T21:38:34-08:00Kidney360Basic Science for Clinicians10.34067/KID.0007812021
- Extracellular Vesicles in Kidney Diseases: Moving ForwardExtracellular vesicles (EVs) are evolving as novel cell mediators, biomarkers and therapeutic targets in kidney health and disease. They are naturally deriving from cells within but also outside the kidney and carry cargo which mirrors the state of the parent cell. Thus, they are potentially more sensitive and disease specific as biomarkers and messengers in various kidney diseases. Beside their role as novel communicators within the nephron they likely communicate between different organs affected by various kidney diseases. Study of urinary EVs can help to fill current knowledge gaps in kidney diseases. However, separation and characterization are challenged by their heterogeneity in size, shape and cargo. Fortunately, more sensitive and direct EV measuring tools are in development. Many clinical syndromes in nephrology from acute to chronic kidney and glomerular to tubular diseases have been studied. Yet validation of biomarkers in larger cohorts is warranted and simpler tools are needed. Translation from in vitro to in vivo studies is also urgently needed. The therapeutic role of urinary EVs in kidney diseases has been studied extensively in rodent models of AKI. Based on the current exponential growth of EV research the field of EV diagnostics and therapeutics is moving forward.ue2u@virginia.edu10.34067/KID.0001892022Sun, 18 Dec 2022 03:21:19 GMT-08:00Extracellular Vesicles in Kidney Diseases: Moving ForwardExtracellular vesicles (EVs) are evolving as novel cell mediators, biomarkers and therapeutic targets in kidney health and disease. They are naturally deriving from cells within but also outside the kidney and carry cargo which mirrors the state of the parent cell. Thus, they are potentially more sensitive and disease specific as biomarkers and messengers in various kidney diseases. Beside their role as novel communicators within the nephron they likely communicate between different organs affected by various kidney diseases. Study of urinary EVs can help to fill current knowledge gaps in kidney diseases. However, separation and characterization are challenged by their heterogeneity in size, shape and cargo. Fortunately, more sensitive and direct EV measuring tools are in development. Many clinical syndromes in nephrology from acute to chronic kidney and glomerular to tubular diseases have been studied. Yet validation of biomarkers in larger cohorts is warranted and simpler tools are needed. Translation from in vitro to in vivo studies is also urgently needed. The therapeutic role of urinary EVs in kidney diseases has been studied extensively in rodent models of AKI. Based on the current exponential growth of EV research the field of EV diagnostics and therapeutics is moving forward.Erdbrügger, UtaHoorn, Ewout J.Le, Thu H.Blijdorp, Charles J.Burger, Dylan2022-12-18T15:21:19-08:00doi:10.34067/KID.0001892022hwp:resource-id:kidney360;KID.0001892022v1American Society of NephrologyCopyright © 2022 American Society of NephrologyKidney360extracellular vesicles, cellular messengers, kidney biomarker, acute and chronic kidney disease, glomerular disease, tubular disease, EV biogenesis, EV detectionBasic Science for CliniciansBasic Science for Cliniciansother202210.34067/KID.00018920222641-76502641-76502022-12-18T15:21:19-08:00Kidney360Basic Science for Clinicians10.34067/KID.0001892022
- Heme Proteins and Kidney Injury: Beyond RhabdomyolysisHeme proteins, the stuff of life, represent an ingenious biologic strategy that capitalizes on the biochemical versatility of heme, and yet is one that avoids the inherent risks to cellular vitality posed by unfettered and promiscuously reactive heme. Heme proteins, however, may be a double-edged sword because they can damage the kidney in certain settings. Although such injury is often viewed mainly within the context of rhabdomyolysis and the nephrotoxicity of myoglobin, an increasing literature now attests to the fact that involvement of heme proteins in renal injury ranges well beyond the confines of this single disease (and its analog, hemolysis); indeed, through the release of the defining heme motif, destabilization of intracellular heme proteins may be a common pathway for acute kidney injury, in general, and irrespective of the underlying insult. This brief review outlines current understanding regarding processes underlying such heme protein-induced acute kidney injury (AKI) and chronic kidney disease (CKD). Topics covered include, among others, the basis for renal injury after the exposure of the kidney to and its incorporation of myoglobin and hemoglobin; auto-oxidation of myoglobin and hemoglobin; destabilization of heme proteins and the release of heme; heme/iron/oxidant pathways of renal injury; generation of reactive oxygen species and reactive nitrogen species by NOX, iNOS, and myeloperoxidase; and the role of circulating cell-free hemoglobin in AKI and CKD. Also covered are the characteristics of the kidney that render this organ uniquely vulnerable to injury after myolysis and hemolysis, and pathobiologic effects emanating from free, labile heme. Mechanisms that defend against the toxicity of heme proteins are discussed, and the review concludes by outlining the therapeutic strategies that have arisen from current understanding of mechanisms of renal injury caused by heme proteins and how such mechanisms may be interrupted.10.34067/KID.0005442022Wed, 05 Oct 2022 09:24:11 GMT-07:00Heme Proteins and Kidney Injury: Beyond RhabdomyolysisHeme proteins, the stuff of life, represent an ingenious biologic strategy that capitalizes on the biochemical versatility of heme, and yet is one that avoids the inherent risks to cellular vitality posed by unfettered and promiscuously reactive heme. Heme proteins, however, may be a double-edged sword because they can damage the kidney in certain settings. Although such injury is often viewed mainly within the context of rhabdomyolysis and the nephrotoxicity of myoglobin, an increasing literature now attests to the fact that involvement of heme proteins in renal injury ranges well beyond the confines of this single disease (and its analog, hemolysis); indeed, through the release of the defining heme motif, destabilization of intracellular heme proteins may be a common pathway for acute kidney injury, in general, and irrespective of the underlying insult. This brief review outlines current understanding regarding processes underlying such heme protein-induced acute kidney injury (AKI) and chronic kidney disease (CKD). Topics covered include, among others, the basis for renal injury after the exposure of the kidney to and its incorporation of myoglobin and hemoglobin; auto-oxidation of myoglobin and hemoglobin; destabilization of heme proteins and the release of heme; heme/iron/oxidant pathways of renal injury; generation of reactive oxygen species and reactive nitrogen species by NOX, iNOS, and myeloperoxidase; and the role of circulating cell-free hemoglobin in AKI and CKD. Also covered are the characteristics of the kidney that render this organ uniquely vulnerable to injury after myolysis and hemolysis, and pathobiologic effects emanating from free, labile heme. Mechanisms that defend against the toxicity of heme proteins are discussed, and the review concludes by outlining the therapeutic strategies that have arisen from current understanding of mechanisms of renal injury caused by heme proteins and how such mechanisms may be interrupted.Nath, Karl A.Singh, Raman DeepCroatt, Anthony J.Adams, Christopher M.2022-10-05T09:24:11-07:00doi:10.34067/KID.0005442022hwp:resource-id:kidney360;3/11/1969American Society of NephrologyCopyright © 2022 by the American Society of NephrologyKidney360acute kidney injury and ICU nephrology, AKI, auto-oxidation, CKD, heme, hemoglobin, hemolysis, myoglobin, rhabdomyolysisBasic Science for CliniciansBasic Science for Cliniciansresearch-article20222022-11-2410.34067/KID.00054420222641-76502022-10-05T09:24:11-07:002022-11-24Kidney360Basic Science for Clinicians31119691979
- The Role of Different Lymphoid Cell Populations in Preeclampsia PathophysiologyPreeclampsia (PE), new-onset hypertension during pregnancy, affects up to 10% of pregnancies worldwide. Despite being the leading cause of maternal and fetal morbidity and mortality, PE has no cure beyond the delivery of the fetal-placental unit. Although the exact pathogenesis of PE is unclear, there is a strong correlation between chronic immune activation; intrauterine growth restriction; uterine artery resistance; dysregulation of the renin-angiotensin system. Which contributes to renal dysfunction; and the resulting hypertension during pregnancy. The genesis of PE is thought to begin with insufficient trophoblast invasion leading to reduced spiral artery remodeling, resulting in decreased placental perfusion and thereby causing placental ischemia. The ischemic placenta releases factors that shower the endothelium and contribute to peripheral vasoconstriction and chronic immune activation and oxidative stress. Studies have shown imbalances in proinflammatory and anti-inflammatory cell types in women with PE and in animal models used to examine mediators of a PE phenotype during pregnancy. T cells, B cells, and natural killer cells have all emerged as potential mediators contributing to the production of vasoactive factors, renal and endothelial dysfunction, mitochondrial dysfunction, and hypertension during pregnancy. The chronic immune activation seen in PE leads to a higher risk for other diseases, such as cardiovascular disease, CKD, dementia during the postpartum period, and PE during a subsequent pregnancy. The purpose of this review is to highlight studies demonstrating the role that different lymphoid cell populations play in the pathophysiology of PE. Moreover, we will discuss treatments focused on restoring immune balance or targeting specific immune mediators that may be potential strategies to improve maternal and fetal outcomes associated with PE.10.34067/KID.0001282022Fri, 12 Aug 2022 01:43:15 GMT-07:00The Role of Different Lymphoid Cell Populations in Preeclampsia PathophysiologyPreeclampsia (PE), new-onset hypertension during pregnancy, affects up to 10% of pregnancies worldwide. Despite being the leading cause of maternal and fetal morbidity and mortality, PE has no cure beyond the delivery of the fetal-placental unit. Although the exact pathogenesis of PE is unclear, there is a strong correlation between chronic immune activation; intrauterine growth restriction; uterine artery resistance; dysregulation of the renin-angiotensin system. Which contributes to renal dysfunction; and the resulting hypertension during pregnancy. The genesis of PE is thought to begin with insufficient trophoblast invasion leading to reduced spiral artery remodeling, resulting in decreased placental perfusion and thereby causing placental ischemia. The ischemic placenta releases factors that shower the endothelium and contribute to peripheral vasoconstriction and chronic immune activation and oxidative stress. Studies have shown imbalances in proinflammatory and anti-inflammatory cell types in women with PE and in animal models used to examine mediators of a PE phenotype during pregnancy. T cells, B cells, and natural killer cells have all emerged as potential mediators contributing to the production of vasoactive factors, renal and endothelial dysfunction, mitochondrial dysfunction, and hypertension during pregnancy. The chronic immune activation seen in PE leads to a higher risk for other diseases, such as cardiovascular disease, CKD, dementia during the postpartum period, and PE during a subsequent pregnancy. The purpose of this review is to highlight studies demonstrating the role that different lymphoid cell populations play in the pathophysiology of PE. Moreover, we will discuss treatments focused on restoring immune balance or targeting specific immune mediators that may be potential strategies to improve maternal and fetal outcomes associated with PE.Campbell, Nathan E.Deer, Evangeline M.Herrock, Owen T.LaMarca, Babbette B.2022-08-12T13:43:15-07:00doi:10.34067/KID.0001282022hwp:resource-id:kidney360;3/10/1785American Society of NephrologyCopyright © 2022 by the American Society of NephrologyKidney360hypertension, basic science, lymphoid cells, preeclampsiaBasic Science for CliniciansBasic Science for Cliniciansresearch-article20222022-10-2710.34067/KID.00012820222641-76502022-08-12T13:43:15-07:002022-10-27Kidney360Basic Science for Clinicians31017851794
- Interferon Gamma contributes to the immune mechanisms of hypertensionHypertension is the leading cause of cardiovascular disease and the primary risk factor for mortality worldwide. For over half a century, researchers have demonstrated that the immunity plays an important role in the development of hypertension; however, the precise mechanisms are still under investigation. The current body of knowledge indicates that pro-inflammatory cytokines may play an important role in contributing to immune-related pathogenesis of hypertension. Interferon gamma (IFNγ), in particular, as an important cytokine that modulates immune responses, has been recently identified as an critical regulator of blood pressure by several groups including us. In this review, we focus on exploring the role of IFNγ in contributing to the pathogenesis of hypertension, outlining the various immune producers of this cytokine and described signaling mechanisms involved. We demonstrate a key role for IFNγ in hypertension through global knockout studies and related downstream signaling pathways that IFNγ production from CD8+ T cell (CD8T) in the kidney promoting CD8T-stimulated salt retention via renal tubule cells, thereby exacerbating hypertension. We discuss potential activators of these T cells described by the current literature and relay a novel hypothesis for activation.SMu@uams.edu10.34067/KID.0001292022Wed, 26 Oct 2022 02:03:07 GMT-07:00Interferon Gamma contributes to the immune mechanisms of hypertensionHypertension is the leading cause of cardiovascular disease and the primary risk factor for mortality worldwide. For over half a century, researchers have demonstrated that the immunity plays an important role in the development of hypertension; however, the precise mechanisms are still under investigation. The current body of knowledge indicates that pro-inflammatory cytokines may play an important role in contributing to immune-related pathogenesis of hypertension. Interferon gamma (IFNγ), in particular, as an important cytokine that modulates immune responses, has been recently identified as an critical regulator of blood pressure by several groups including us. In this review, we focus on exploring the role of IFNγ in contributing to the pathogenesis of hypertension, outlining the various immune producers of this cytokine and described signaling mechanisms involved. We demonstrate a key role for IFNγ in hypertension through global knockout studies and related downstream signaling pathways that IFNγ production from CD8+ T cell (CD8T) in the kidney promoting CD8T-stimulated salt retention via renal tubule cells, thereby exacerbating hypertension. We discuss potential activators of these T cells described by the current literature and relay a novel hypothesis for activation.Benson, Lance N.Liu, YunmengDeck, Katherine SMora, ChristophMu, Shengyu2022-10-26T14:03:07-07:00doi:10.34067/KID.0001292022hwp:resource-id:kidney360;KID.0001292022v1American Society of NephrologyCopyright © 2022 American Society of NephrologyKidney360immunity and inflammation, Interferon-gamma, HypertensionBasic Science for CliniciansBasic Science for Cliniciansother202210.34067/KID.00012920222641-76502641-76502022-10-26T14:03:07-07:00Kidney360Basic Science for Clinicians3312122164216410.34067/KID.000129202221732173
- Role of GSTM1 in hypertension, chronic kidney disease and related diseases across the lifespanOver twenty years after the introduction of angiotensin converting enzyme inhibitors and angiotensin receptor blockers, chronic kidney disease (CKD) remains a major public health burden with very limited therapeutic options to halt or slow kidney disease progression at all ages. The general consensus is that oxidative stress contributes to CKD development and progression. Yet, to date, there is no clear evidence that broad use of antioxidant therapy provides a beneficial effect in CKD. Understanding the specific pathophysiologic mechanisms in those who are genetically most susceptible to oxidative stress is a crucial step to inform therapy in an individualized medicine approach, taking into account differing exposures and risks across the lifespan. GSTM1 (glutathione-S-transferase mu 1) is a phase II enzyme involved in inactivation of reactive oxygen species and metabolism of xenobiotics. In particular, those with the highly prevalent GSTM1 null genotype (GSTM1(0/0)) may be more susceptible to kidney disease progression due to impaired capacity to handle the increased oxidative stress burden in disease states and might specifically benefit from therapy that targets the redox imbalance mediated by loss of GSTM1 enzyme. In this review, we will discuss the studies implicating the role of GSTM1 deficiency in kidney and related diseases from experimental rodent models to humans, from the prenatal period through senescence, and the potential underlying mechanism.Thu_Le@URMC.Rochester.edu10.34067/KID.0004552022Wed, 19 Oct 2022 04:33:59 GMT-07:00Role of GSTM1 in hypertension, chronic kidney disease and related diseases across the lifespanOver twenty years after the introduction of angiotensin converting enzyme inhibitors and angiotensin receptor blockers, chronic kidney disease (CKD) remains a major public health burden with very limited therapeutic options to halt or slow kidney disease progression at all ages. The general consensus is that oxidative stress contributes to CKD development and progression. Yet, to date, there is no clear evidence that broad use of antioxidant therapy provides a beneficial effect in CKD. Understanding the specific pathophysiologic mechanisms in those who are genetically most susceptible to oxidative stress is a crucial step to inform therapy in an individualized medicine approach, taking into account differing exposures and risks across the lifespan. GSTM1 (glutathione-S-transferase mu 1) is a phase II enzyme involved in inactivation of reactive oxygen species and metabolism of xenobiotics. In particular, those with the highly prevalent GSTM1 null genotype (GSTM1(0/0)) may be more susceptible to kidney disease progression due to impaired capacity to handle the increased oxidative stress burden in disease states and might specifically benefit from therapy that targets the redox imbalance mediated by loss of GSTM1 enzyme. In this review, we will discuss the studies implicating the role of GSTM1 deficiency in kidney and related diseases from experimental rodent models to humans, from the prenatal period through senescence, and the potential underlying mechanism.Levy, RebeccaLe, Thu H.2022-10-19T04:33:59-07:00doi:10.34067/KID.0004552022hwp:resource-id:kidney360;KID.0004552022v1American Society of NephrologyCopyright © 2022 American Society of NephrologyKidney360GSTM1, oxidative stress, chronic kidney disease, hypertensionBasic Science for CliniciansBasic Science for Cliniciansother202210.34067/KID.00045520222641-76502641-76502022-10-19T04:33:59-07:00Kidney360Basic Science for Clinicians3312122153215310.34067/KID.000455202221632163
- Dendritic Cell Epithelial Sodium Channel in Inflammation, Salt-Sensitive Hypertension, and Kidney DamageSalt-sensitive hypertension is a major risk factor for cardiovascular morbidity and mortality. The pathophysiologic mechanisms leading to different individual BP responses to changes in dietary salt remain elusive. Research in the last two decades revealed that the immune system plays a critical role in the development of hypertension and related end organ damage. Moreover, sodium accumulates nonosmotically in human tissue, including the skin and muscle, shifting the dogma on body sodium balance and its regulation. Emerging evidence suggests that high concentrations of extracellular sodium can directly trigger an inflammatory response in antigen-presenting cells (APCs), leading to hypertension and vascular and renal injury. Importantly, sodium entry into APCs is mediated by the epithelial sodium channel (ENaC). Although the role of the ENaC in renal regulation of sodium excretion and BP is well established, these new findings imply that the ENaC may also exert BP modulatory effects in extrarenal tissue through an immune-dependent pathway. In this review, we discuss the recent advances in our understanding of the pathophysiology of salt-sensitive hypertension with a particular focus on the roles of APCs and the extrarenal ENaC.10.34067/KID.0001272022Mon, 27 Jun 2022 12:01:40 GMT-07:00Dendritic Cell Epithelial Sodium Channel in Inflammation, Salt-Sensitive Hypertension, and Kidney DamageSalt-sensitive hypertension is a major risk factor for cardiovascular morbidity and mortality. The pathophysiologic mechanisms leading to different individual BP responses to changes in dietary salt remain elusive. Research in the last two decades revealed that the immune system plays a critical role in the development of hypertension and related end organ damage. Moreover, sodium accumulates nonosmotically in human tissue, including the skin and muscle, shifting the dogma on body sodium balance and its regulation. Emerging evidence suggests that high concentrations of extracellular sodium can directly trigger an inflammatory response in antigen-presenting cells (APCs), leading to hypertension and vascular and renal injury. Importantly, sodium entry into APCs is mediated by the epithelial sodium channel (ENaC). Although the role of the ENaC in renal regulation of sodium excretion and BP is well established, these new findings imply that the ENaC may also exert BP modulatory effects in extrarenal tissue through an immune-dependent pathway. In this review, we discuss the recent advances in our understanding of the pathophysiology of salt-sensitive hypertension with a particular focus on the roles of APCs and the extrarenal ENaC.Ertuglu, Lale A.Kirabo, Annet2022-06-27T12:01:40-07:00doi:10.34067/KID.0001272022hwp:resource-id:kidney360;3/9/1620American Society of NephrologyCopyright © 2022 by the American Society of NephrologyKidney360hypertension, dendritic cell, hypertension, inflammation, isolevuglandins, salt sensitivity, sodiumBasic Science for CliniciansBasic Science for Cliniciansresearch-article20222022-09-2910.34067/KID.00012720222641-76502022-06-27T12:01:40-07:002022-09-29Kidney360Basic Science for Clinicians3916201629
- Polycystic Ovary Syndrome: Insights from Preclinical ResearchPolycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, affecting approximately 10%. PCOS is diagnosed by the presence of at least two of these three criteria: hyperandrogenemia, oligo- or anovulation, and polycystic ovaries. The most common type (80%) of PCOS includes hyperandrogenemia. PCOS is also characterized by obesity or overweight (in 80% of US women with PCOS), insulin resistance with elevated plasma insulin but not necessarily hyperglycemia, dyslipidemia, proteinuria, and elevated BP. Although elevated compared with age-matched controls, BP may not reach levels considered treatable according to the current clinical hypertension guidelines. However, it is well known that elevated BP, even modestly so, increases the risk of cardiovascular disease. We have developed a model of hyperandrogenemia in rodents that mimics the characteristics of PCOS in women, with increases in body weight, insulin resistance, dyslipidemia, andproteinuria and elevated BP. This review discusses potential mechanisms responsible for the elevated BP in the adult and aging PCOS rat model that may be extrapolated to women with PCOS.10.34067/KID.0002052022Fri, 17 Jun 2022 01:26:06 GMT-07:00Polycystic Ovary Syndrome: Insights from Preclinical ResearchPolycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, affecting approximately 10%. PCOS is diagnosed by the presence of at least two of these three criteria: hyperandrogenemia, oligo- or anovulation, and polycystic ovaries. The most common type (80%) of PCOS includes hyperandrogenemia. PCOS is also characterized by obesity or overweight (in 80% of US women with PCOS), insulin resistance with elevated plasma insulin but not necessarily hyperglycemia, dyslipidemia, proteinuria, and elevated BP. Although elevated compared with age-matched controls, BP may not reach levels considered treatable according to the current clinical hypertension guidelines. However, it is well known that elevated BP, even modestly so, increases the risk of cardiovascular disease. We have developed a model of hyperandrogenemia in rodents that mimics the characteristics of PCOS in women, with increases in body weight, insulin resistance, dyslipidemia, andproteinuria and elevated BP. This review discusses potential mechanisms responsible for the elevated BP in the adult and aging PCOS rat model that may be extrapolated to women with PCOS.Reckelhoff, Jane F.Shawky, Noha M.Romero, Damian G.Yanes Cardozo, Licy L.2022-06-17T13:26:06-07:00doi:10.34067/KID.0002052022hwp:resource-id:kidney360;3/8/1449American Society of NephrologyCopyright © 2022 by the American Society of NephrologyKidney360hypertension, aging, basic science, blood pressure, hyperandrogenemia, obesity, polycystic ovary syndrome, pregnancy, renin-angiotensin systemBasic Science for CliniciansBasic Science for Cliniciansresearch-article20222022-08-2510.34067/KID.00020520222641-76502022-06-17T13:26:06-07:002022-08-25Kidney360Basic Science for Clinicians3814491457
- Novel Function for Bilirubin as a Metabolic Signaling Molecule: Implications for Kidney DiseasesBilirubin is the end product of the catabolism of heme via the heme oxygenase pathway. Heme oxygenase generates carbon monoxide (CO) and biliverdin from the breakdown of heme, and biliverdin is rapidly reduced to bilirubin by the enzyme biliverdin reductase (BVR). Bilirubin has long been thought of as a toxic product that is only relevant to health when blood levels are severely elevated, such as in clinical jaundice. The physiologic functions of bilirubin correlate with the growing body of evidence demonstrating the protective effects of serum bilirubin against cardiovascular and metabolic diseases. Although the correlative evidence suggests a protective effect of serum bilirubin against many diseases, the mechanism by which bilirubin offers protection against cardiovascular and metabolic diseases remains unanswered. We recently discovered a novel function for bilirubin as a signaling molecule capable of activating the peroxisome proliferator-activated receptor α (PPARα) transcription factor. This review summarizes the new finding of bilirubin as a signaling molecule and proposes several mechanisms by which this novel action of bilirubin may protect against cardiovascular and kidney diseases.10.34067/KID.0000062022Fri, 25 Mar 2022 01:37:16 GMT-07:00Novel Function for Bilirubin as a Metabolic Signaling Molecule: Implications for Kidney DiseasesBilirubin is the end product of the catabolism of heme via the heme oxygenase pathway. Heme oxygenase generates carbon monoxide (CO) and biliverdin from the breakdown of heme, and biliverdin is rapidly reduced to bilirubin by the enzyme biliverdin reductase (BVR). Bilirubin has long been thought of as a toxic product that is only relevant to health when blood levels are severely elevated, such as in clinical jaundice. The physiologic functions of bilirubin correlate with the growing body of evidence demonstrating the protective effects of serum bilirubin against cardiovascular and metabolic diseases. Although the correlative evidence suggests a protective effect of serum bilirubin against many diseases, the mechanism by which bilirubin offers protection against cardiovascular and metabolic diseases remains unanswered. We recently discovered a novel function for bilirubin as a signaling molecule capable of activating the peroxisome proliferator-activated receptor α (PPARα) transcription factor. This review summarizes the new finding of bilirubin as a signaling molecule and proposes several mechanisms by which this novel action of bilirubin may protect against cardiovascular and kidney diseases.Stec, David E.Tiribelli, ClaudioBadmus, Olufunto O.Hinds, Terry D.2022-03-25T13:37:16-07:00doi:10.34067/KID.0000062022hwp:resource-id:kidney360;3/5/945American Society of NephrologyCopyright © 2022 by the American Society of NephrologyKidney360renal physiology, acute kidney injury, basic science, bilirubin, biliverdin reductase-A, cardiovascular disease, heme oxygenase, hormone, hypertension, kidney disease, peroxisome proliferator-activated receptor, PPARαBasic Science for CliniciansRenal PhysiologyBasic Science for CliniciansRenal Physiologyresearch-article20222022-05-2610.34067/KID.00000620222641-76502022-03-25T13:37:16-07:002022-05-26Kidney360Basic Science for Clinicians35945953
- SGLT2 Inhibitors: Physiology and PharmacologySGLTs are sodium glucose transporters found on the luminal membrane of the proximal tubule, where they reabsorb some 180 g (1 mol) of glucose from the glomerular filtrate each day. The natural glucoside phlorizin completely blocks glucose reabsorption. Oral SGLT2 inhibitors are rapidly absorbed into the blood stream, where theyremain in the circulation for hours. On glomerular filtration, they bind specifically to SGLT2 in the luminal membrane of the early proximal tubule to reduce glucose reabsorption by 50%–60%. Because of glucose excretion, these drugs lower plasma glucose and glycosylated hemoglobin levels in patients with type 2 diabetes mellitus. The drugs also protect against heart and renal failure. The aim of this review is to summarize what is known about the physiology of renal SGLTs and the pharmacology of SGLT drugs.10.34067/KID.0002772021Fri, 17 Sep 2021 09:47:50 GMT-07:00SGLT2 Inhibitors: Physiology and PharmacologySGLTs are sodium glucose transporters found on the luminal membrane of the proximal tubule, where they reabsorb some 180 g (1 mol) of glucose from the glomerular filtrate each day. The natural glucoside phlorizin completely blocks glucose reabsorption. Oral SGLT2 inhibitors are rapidly absorbed into the blood stream, where theyremain in the circulation for hours. On glomerular filtration, they bind specifically to SGLT2 in the luminal membrane of the early proximal tubule to reduce glucose reabsorption by 50%–60%. Because of glucose excretion, these drugs lower plasma glucose and glycosylated hemoglobin levels in patients with type 2 diabetes mellitus. The drugs also protect against heart and renal failure. The aim of this review is to summarize what is known about the physiology of renal SGLTs and the pharmacology of SGLT drugs.Wright, Ernest M.2021-09-17T09:47:50-07:00doi:10.34067/KID.0002772021hwp:resource-id:kidney360;2/12/2027American Society of NephrologyCopyright © 2021 by the American Society of NephrologyKidney360renal physiology, basic science, diabetes, glucose, heart failure, inhibitors, SGLT, SGLT2, sodium glucose transportersBasic Science for CliniciansBasic Science for Cliniciansresearch-article20212021-12-3010.34067/KID.00027720212641-76502021-09-17T09:47:50-07:002021-12-30Kidney360Basic Science for Clinicians21220272037
- Myeloid Heterogeneity in Kidney Disease as Revealed through Single-Cell RNA SequencingKidney disease represents a global health burden of increasing prevalence and is an independent risk factor for cardiovascular disease. Myeloid cells are a major cellular compartment of the immune system; they are found in the healthy kidney and in increased numbers in the damaged and/or diseased kidney, where they act as key players in the progression of injury, inflammation, and fibrosis. They possess enormous plasticity and heterogeneity, adopting different phenotypic and functional characteristics in response to stimuli in the local milieu. Although this inherent complexity remains to be fully understood in the kidney, advances in single-cell genomics promise to change this. Specifically, single-cell RNA sequencing (scRNA-seq) has had a transformative effect on kidney research, enabling the profiling and analysis of the transcriptomes of single cells at unprecedented resolution and throughput, and subsequent generation of cell atlases. Moving forward, combining scRNA- and single-nuclear RNA-seq with greater-resolution spatial transcriptomics will allow spatial mapping of kidney disease of varying etiology to further reveal the patterning of immune cells and nonimmune renal cells. This review summarizes the roles of myeloid cells in kidney health and disease, the experimental workflow in currently available scRNA-seq technologies, and published findings using scRNA-seq in the context of myeloid cells and the kidney.10.34067/KID.0003682021Thu, 02 Sep 2021 11:34:30 GMT-07:00Myeloid Heterogeneity in Kidney Disease as Revealed through Single-Cell RNA SequencingKidney disease represents a global health burden of increasing prevalence and is an independent risk factor for cardiovascular disease. Myeloid cells are a major cellular compartment of the immune system; they are found in the healthy kidney and in increased numbers in the damaged and/or diseased kidney, where they act as key players in the progression of injury, inflammation, and fibrosis. They possess enormous plasticity and heterogeneity, adopting different phenotypic and functional characteristics in response to stimuli in the local milieu. Although this inherent complexity remains to be fully understood in the kidney, advances in single-cell genomics promise to change this. Specifically, single-cell RNA sequencing (scRNA-seq) has had a transformative effect on kidney research, enabling the profiling and analysis of the transcriptomes of single cells at unprecedented resolution and throughput, and subsequent generation of cell atlases. Moving forward, combining scRNA- and single-nuclear RNA-seq with greater-resolution spatial transcriptomics will allow spatial mapping of kidney disease of varying etiology to further reveal the patterning of immune cells and nonimmune renal cells. This review summarizes the roles of myeloid cells in kidney health and disease, the experimental workflow in currently available scRNA-seq technologies, and published findings using scRNA-seq in the context of myeloid cells and the kidney.Bell, Rachel M.B.Denby, Laura2021-09-02T11:34:30-07:00doi:10.34067/KID.0003682021hwp:resource-id:kidney360;2/11/1844American Society of NephrologyCopyright © 2021 by the American Society of NephrologyKidney360chronic kidney disease, basic science, dendritic cells, kidney disease, macrophage, monocytes, myeloid cells, scRNA-sequencing, sequence analysis, RNABasic Science for CliniciansBasic Science for Cliniciansresearch-article20212021-11-2510.34067/KID.00036820212641-76502021-09-02T11:34:30-07:002021-11-25Kidney360Basic Science for Clinicians21118441851
- Multi-Target Drugs for Kidney DiseasesKidney diseases such as AKI, CKD, and GN can lead to dialysis and the need for kidney transplantation. The pathologies for kidney diseases are extremely complex, progress at different rates, and involve several cell types and cell signaling pathways. Complex kidney diseases require therapeutics that can act on multiple targets. In the past 10 years, in silico design of drugs has allowed for multi-target drugs to progress quickly from concept to reality. Several multi-target drugs have been made successfully to target AA pathways and transcription factors for the treatment of inflammatory, fibrotic, and metabolic diseases. Multi-target drugs have also demonstrated great potential to treat diabetic nephropathy and fibrotic kidney disease. These drugs act by decreasing renal TGF-β signaling, inflammation, mitochondrial dysfunction, and oxidative stress. There are several other recently developed multi-target drugs that have yet to be tested for their ability to combat kidney diseases. Overall, there is excellent potential for multi-target drugs that act on several cell types and signaling pathways to treat kidney diseases.10.34067/KID.0003582021Mon, 02 Aug 2021 01:50:51 GMT-07:00Multi-Target Drugs for Kidney DiseasesKidney diseases such as AKI, CKD, and GN can lead to dialysis and the need for kidney transplantation. The pathologies for kidney diseases are extremely complex, progress at different rates, and involve several cell types and cell signaling pathways. Complex kidney diseases require therapeutics that can act on multiple targets. In the past 10 years, in silico design of drugs has allowed for multi-target drugs to progress quickly from concept to reality. Several multi-target drugs have been made successfully to target AA pathways and transcription factors for the treatment of inflammatory, fibrotic, and metabolic diseases. Multi-target drugs have also demonstrated great potential to treat diabetic nephropathy and fibrotic kidney disease. These drugs act by decreasing renal TGF-β signaling, inflammation, mitochondrial dysfunction, and oxidative stress. There are several other recently developed multi-target drugs that have yet to be tested for their ability to combat kidney diseases. Overall, there is excellent potential for multi-target drugs that act on several cell types and signaling pathways to treat kidney diseases.Imig, John D.Merk, DanielProschak, Eugen2021-08-02T13:50:51-07:00doi:10.34067/KID.0003582021hwp:resource-id:kidney360;2/10/1645American Society of NephrologyCopyright © 2021 by the American Society of NephrologyKidney360nephro-pharmacology, basic science, chronic kidney disease, diabetes, drug delivery systems, eicosanoids, fatty acids, hypertension, kidney diseases, multi-ligand drugs, pharmaceutical preparations, transcription factorsBasic Science for CliniciansBasic Science for Cliniciansresearch-article20212021-10-2810.34067/KID.00035820212641-76502021-08-02T13:50:51-07:002021-10-28Kidney360Basic Science for Clinicians21016451653
- Monocytes and Macrophages in Kidney Transplantation and Insights from Single Cell RNA-Seq StudiesSingle-cell RNA sequencing (scRNA-seq) is a powerful technology that allows for the identification of minority cell types in complex tissues, such as immune cells in the kidney. Previously, gene expression from infrequent cell types was missed using bulk RNA-sequencing methods due to an averaging effect. Additionally, scRNA-seq facilitates assignment of cell origin in a sample, a shortcoming of previous bulk sequencing technologies. Thus, scRNA-seq is ideal to study the immune cell landscape and the alloimmune response in the human kidney transplant. However, there are few studies published to date. Macrophages are known to play an important role in health and disease in the kidney. Furthermore, it is known that macrophages play key roles in rejection of the kidney transplant. The definition, ontogeny, and function of these cells is complex and nomenclature has evolved as new technologies have become available. In this review, an overview is provided of monocyte and macrophage nomenclature, ontogeny, and function, with a specific focus on kidney transplantation, and including novel scRNA-seq findings. scRNA-seq offers an unbiased transcriptional approach to defining macrophages and provides insights into macrophage ontogeny and function not possible with contemporary methods.10.34067/KID.0003842021Tue, 17 Aug 2021 01:18:43 GMT-07:00Monocytes and Macrophages in Kidney Transplantation and Insights from Single Cell RNA-Seq StudiesSingle-cell RNA sequencing (scRNA-seq) is a powerful technology that allows for the identification of minority cell types in complex tissues, such as immune cells in the kidney. Previously, gene expression from infrequent cell types was missed using bulk RNA-sequencing methods due to an averaging effect. Additionally, scRNA-seq facilitates assignment of cell origin in a sample, a shortcoming of previous bulk sequencing technologies. Thus, scRNA-seq is ideal to study the immune cell landscape and the alloimmune response in the human kidney transplant. However, there are few studies published to date. Macrophages are known to play an important role in health and disease in the kidney. Furthermore, it is known that macrophages play key roles in rejection of the kidney transplant. The definition, ontogeny, and function of these cells is complex and nomenclature has evolved as new technologies have become available. In this review, an overview is provided of monocyte and macrophage nomenclature, ontogeny, and function, with a specific focus on kidney transplantation, and including novel scRNA-seq findings. scRNA-seq offers an unbiased transcriptional approach to defining macrophages and provides insights into macrophage ontogeny and function not possible with contemporary methods.Malone, Andrew F.2021-08-17T13:18:43-07:00doi:10.34067/KID.0003842021hwp:resource-id:kidney360;2/10/1654American Society of NephrologyCopyright © 2021 by the American Society of NephrologyKidney360transplantation, allografts, basic science, biopsy, kidney transplant, macrophage, monocytes, scRNA-seq, transcriptome, transplantationBasic Science for CliniciansBasic Science for Cliniciansresearch-article20212021-10-2810.34067/KID.00038420212641-76502021-08-17T13:18:43-07:002021-10-28Kidney360Basic Science for Clinicians21016541659
- Renal Sensing of Bacterial Metabolites in the Gut-kidney AxisSeminal works have now revealed the gut microbiota is connected with several diseases, including renal disorders. The balance between optimal and dysregulated host-microbiota interactions has completely changed our understanding of immunity and inflammation. Kidney injury is associated with accumulation of uremic toxins in the intestine, augmented intestinal permeability, and systemic inflammation. Intestinal bacteria can signal through innate receptors and induce immune cell activation in the lamina propria and release of inflammatory mediators into the bloodstream . But the gut microbiota can also modulate immune functions through soluble products as short-chain fatty acids (SCFAs). The three most common SCFAs are propionate, butyrate, and acetate, which can signal through specific G-protein coupled receptors (GPCRs), such as GPR43, GPR41, and GPR109a, expressed on the surface of epithelial, myeloid, endothelial, and immune cells, among others. The triggered signaling can change cell metabolism, immune cell activation, and cell death. In this study, we reviewed the gut-kidney axis, how kidney cells can sense SCFAs, and its implication in kidney diseases.10.34067/KID.0000292021Fri, 02 Jul 2021 11:27:00 GMT-07:00Renal Sensing of Bacterial Metabolites in the Gut-kidney AxisSeminal works have now revealed the gut microbiota is connected with several diseases, including renal disorders. The balance between optimal and dysregulated host-microbiota interactions has completely changed our understanding of immunity and inflammation. Kidney injury is associated with accumulation of uremic toxins in the intestine, augmented intestinal permeability, and systemic inflammation. Intestinal bacteria can signal through innate receptors and induce immune cell activation in the lamina propria and release of inflammatory mediators into the bloodstream . But the gut microbiota can also modulate immune functions through soluble products as short-chain fatty acids (SCFAs). The three most common SCFAs are propionate, butyrate, and acetate, which can signal through specific G-protein coupled receptors (GPCRs), such as GPR43, GPR41, and GPR109a, expressed on the surface of epithelial, myeloid, endothelial, and immune cells, among others. The triggered signaling can change cell metabolism, immune cell activation, and cell death. In this study, we reviewed the gut-kidney axis, how kidney cells can sense SCFAs, and its implication in kidney diseases.Foresto-Neto, OrestesGhirotto, BrunoCâmara, Niels Olsen Saraiva2021-07-02T11:27:00-07:00doi:10.34067/KID.0000292021hwp:resource-id:kidney360;2/9/1501American Society of NephrologyCopyright © 2021 by the American Society of NephrologyKidney360renal physiology, AKI, basic science, CKD, gastrointestinal microbiome, GCPR, inflammation, short chain fatty acidsBasic Science for CliniciansBasic Science for Cliniciansresearch-article20212021-09-3010.34067/KID.00002920212641-76502021-07-02T11:27:00-07:002021-09-30Kidney360Basic Science for Clinicians2915011509
- The Sniffing Kidney: Roles for Renal Olfactory Receptors in Health and DiseaseOlfactory receptors (ORs) represent the largest gene family in the human genome. Despite their name, functions exist for these receptors outside of the nose. Among the tissues known to take advantage of OR signaling is the kidney. From mouse to man, the list of renal ORs continues to expand, and they have now been linked to a variety of processes involved in the maintenance of renal homeostasis, including the modulation of blood pressure, response to acidemia, and the development of diabetes. In this review, we highlight the recent progress made on the growing appreciation for renal ORs in physiology and pathophysiology.10.34067/KID.0000712021Mon, 19 Apr 2021 02:13:27 GMT-07:00The Sniffing Kidney: Roles for Renal Olfactory Receptors in Health and DiseaseOlfactory receptors (ORs) represent the largest gene family in the human genome. Despite their name, functions exist for these receptors outside of the nose. Among the tissues known to take advantage of OR signaling is the kidney. From mouse to man, the list of renal ORs continues to expand, and they have now been linked to a variety of processes involved in the maintenance of renal homeostasis, including the modulation of blood pressure, response to acidemia, and the development of diabetes. In this review, we highlight the recent progress made on the growing appreciation for renal ORs in physiology and pathophysiology.Shepard, Blythe D.2021-04-19T14:13:27-07:00doi:10.34067/KID.0000712021hwp:resource-id:kidney360;2/6/1056American Society of NephrologyCopyright © 2021 by the American Society of NephrologyKidney360renal physiology, acidemia, basic science, blood pressure, diabetes, GPCR, odorant receptors, olfactory receptorBasic Science for CliniciansBasic Science for Cliniciansresearch-article20212021-06-2410.34067/KID.00007120212641-76502021-04-19T14:13:27-07:002021-06-24Kidney360Basic Science for Clinicians2610561062
- Podocyte Lipotoxicity in CKDCKD represents the ninth most common cause of death in the United States but, despite this large health burden, treatment options for affected patients remain limited. To remedy this, several relevant pathways have been identified that may lead to novel therapeutic options. Among them, altered renal lipid metabolism, first described in 1982, has been recognized as a common pathway in clinical and experimental CKD of both metabolic and nonmetabolic origin. This observation has led many researchers to investigate the cause of this renal parenchyma lipid accumulation and its downstream effect on renal structure and function. Among key cellular components of the kidney parenchyma, podocytes are terminally differentiated cells that cannot be easily replaced when lost. Clinical and experimental evidence supports a role of reduced podocyte number in the progression of CKD. Given the importance of the podocytes in the maintenance of the glomerular filtration barrier and the accumulation of TG and cholesterol-rich lipid droplets in the podocyte and glomerulus in kidney diseases that cause CKD, understanding the upstream cause and downstream consequences of lipid accumulation in podocytes may lead to novel therapeutic opportunities. In this review, we hope to consolidate our understanding of the causes and consequences of dysregulated renal lipid metabolism in CKD development and progression, with a major focus on podocytes.10.34067/KID.0006152020Fri, 26 Feb 2021 09:59:35 GMT-08:00Podocyte Lipotoxicity in CKDCKD represents the ninth most common cause of death in the United States but, despite this large health burden, treatment options for affected patients remain limited. To remedy this, several relevant pathways have been identified that may lead to novel therapeutic options. Among them, altered renal lipid metabolism, first described in 1982, has been recognized as a common pathway in clinical and experimental CKD of both metabolic and nonmetabolic origin. This observation has led many researchers to investigate the cause of this renal parenchyma lipid accumulation and its downstream effect on renal structure and function. Among key cellular components of the kidney parenchyma, podocytes are terminally differentiated cells that cannot be easily replaced when lost. Clinical and experimental evidence supports a role of reduced podocyte number in the progression of CKD. Given the importance of the podocytes in the maintenance of the glomerular filtration barrier and the accumulation of TG and cholesterol-rich lipid droplets in the podocyte and glomerulus in kidney diseases that cause CKD, understanding the upstream cause and downstream consequences of lipid accumulation in podocytes may lead to novel therapeutic opportunities. In this review, we hope to consolidate our understanding of the causes and consequences of dysregulated renal lipid metabolism in CKD development and progression, with a major focus on podocytes.Kim, Jin-JuWilbon, Sydney S.Fornoni, Alessia2021-02-26T09:59:35-08:00doi:10.34067/KID.0006152020hwp:resource-id:kidney360;2/4/755American Society of NephrologyCopyright © 2021 by the American Society of NephrologyKidney360chronic kidney disease, basic science, lipid accumulation, podocyte lipotoxicityBasic Science for CliniciansBasic Science for Cliniciansresearch-article20212021-04-2910.34067/KID.00061520202641-76502021-02-26T09:59:35-08:002021-04-29Kidney360Basic Science for Clinicians24755762
- Progress toward the Clinical Application of Mesenchymal Stromal Cells and Other Disease-Modulating Regenerative Therapies: Examples from the Field of NephrologyDrawing from basic knowledge of stem-cell biology, embryonic development, wound healing, and aging, regenerative medicine seeks to develop therapeutic strategies that complement or replace conventional treatments by actively repairing diseased tissue or generating new organs and tissues. Among the various clinical-translational strategies within the field of regenerative medicine, several can be broadly described as promoting disease resolution indirectly through local or systemic interactions with a patient’s cells, without permanently integrating or directly forming new primary tissue. In this review, we focus on such therapies, which we term disease-modulating regenerative therapies (DMRT), and on the extent to which they have been translated into the clinical arena in four distinct areas of nephrology: renovascular disease (RVD), sepsis-associated AKI (SA-AKI), diabetic kidney disease (DKD), and kidney transplantation (KTx). As we describe, the DMRT that has most consistently progressed to human clinical trials for these indications is mesenchymal stem/stromal cells (MSCs), which potently modulate ischemic, inflammatory, profibrotic, and immune-mediated tissue injury through diverse paracrine mechanisms. In KTx, several early-phase clinical trials have also tested the potential for ex vivo–expanded regulatory immune cell therapies to promote donor-specific tolerance and prevent or resolve allograft injury. Other promising DMRT, including adult stem/progenitor cells, stem cell–derived extracellular vesicles, and implantable hydrogels/biomaterials remain at varying preclinical stages of translation for these renal conditions. To date (2021), no DMRT has gained market approval for use in patients with RVD, SA-AKI, DKD, or KTx, and clinical trials demonstrating definitive, cost-effective patient benefits are needed. Nonetheless, exciting progress in understanding the disease-specific mechanisms of action of MSCs and other DMRT, coupled with increasing knowledge of the pathophysiologic basis for renal-tissue injury and the experience gained from pioneering early-phase clinical trials provide optimism that influential, regenerative treatments for diverse kidney diseases will emerge in the years ahead.10.34067/KID.0005692020Wed, 27 Jan 2021 01:35:26 GMT-08:00Progress toward the Clinical Application of Mesenchymal Stromal Cells and Other Disease-Modulating Regenerative Therapies: Examples from the Field of NephrologyDrawing from basic knowledge of stem-cell biology, embryonic development, wound healing, and aging, regenerative medicine seeks to develop therapeutic strategies that complement or replace conventional treatments by actively repairing diseased tissue or generating new organs and tissues. Among the various clinical-translational strategies within the field of regenerative medicine, several can be broadly described as promoting disease resolution indirectly through local or systemic interactions with a patient’s cells, without permanently integrating or directly forming new primary tissue. In this review, we focus on such therapies, which we term disease-modulating regenerative therapies (DMRT), and on the extent to which they have been translated into the clinical arena in four distinct areas of nephrology: renovascular disease (RVD), sepsis-associated AKI (SA-AKI), diabetic kidney disease (DKD), and kidney transplantation (KTx). As we describe, the DMRT that has most consistently progressed to human clinical trials for these indications is mesenchymal stem/stromal cells (MSCs), which potently modulate ischemic, inflammatory, profibrotic, and immune-mediated tissue injury through diverse paracrine mechanisms. In KTx, several early-phase clinical trials have also tested the potential for ex vivo–expanded regulatory immune cell therapies to promote donor-specific tolerance and prevent or resolve allograft injury. Other promising DMRT, including adult stem/progenitor cells, stem cell–derived extracellular vesicles, and implantable hydrogels/biomaterials remain at varying preclinical stages of translation for these renal conditions. To date (2021), no DMRT has gained market approval for use in patients with RVD, SA-AKI, DKD, or KTx, and clinical trials demonstrating definitive, cost-effective patient benefits are needed. Nonetheless, exciting progress in understanding the disease-specific mechanisms of action of MSCs and other DMRT, coupled with increasing knowledge of the pathophysiologic basis for renal-tissue injury and the experience gained from pioneering early-phase clinical trials provide optimism that influential, regenerative treatments for diverse kidney diseases will emerge in the years ahead.Hickson, LaTonya J.Herrmann, Sandra M.McNicholas, Bairbre A.Griffin, Matthew D.2021-01-27T13:35:26-08:00doi:10.34067/KID.0005692020hwp:resource-id:kidney360;2/3/542American Society of NephrologyCopyright © 2021 by the American Society of NephrologyKidney360chronic kidney disease, basic science, clinical trials, diabetic kidney disease, inflammation, mesenchymal stromal cells, regenerative medicine, regulatory T cells, renovascular disease, senescence, sepsis, stem cellsBasic Science for CliniciansBasic Science for Cliniciansother20212021-03-2510.34067/KID.00056920202641-76502021-01-27T13:35:26-08:002021-03-25Kidney360Basic Science for Clinicians23542557
- Sphingolipids and Kidney Disease: Possible Role of Preeclampsia and Intrauterine Growth Restriction (IUGR)Sphingolipids are now considered not only as constitutional components of the cellular membrane but also as essential bioactive factors regulating development and physiologic functions. Ceramide is a vital intermediate of sphingolipid metabolism, synthesized by de novo and salvage pathways, producing multiple types of sphingolipids and their metabolites. Although mutations in gene-encoding enzymes regulating sphingolipid synthesis and metabolism cause distinct diseases, an abnormal sphingolipid metabolism contributes to various pathologic conditions, including kidney diseases. Excessive accumulation of glycosphingolipids and promotion of the ceramide salvage and sphingosine-1-phosphate (S1P) pathways are found in the damaged kidney. Acceleration of the sphingosine kinase/S1P/S1P receptor (SphK/S1P/S1PR) axis plays a central role in deteriorating kidney functions. The SphK/S1P/S1PR signaling impairment is also found during pregnancy complications, such as preeclampsia and intrauterine growth restriction (IUGR). This mini-review discusses the current state of knowledge regarding the role of sphingolipid metabolism on kidney diseases, and the possible involvement of preeclampsia and IUGR conditions.10.34067/KID.0006322020Thu, 07 Jan 2021 11:41:55 GMT-08:00Sphingolipids and Kidney Disease: Possible Role of Preeclampsia and Intrauterine Growth Restriction (IUGR)Sphingolipids are now considered not only as constitutional components of the cellular membrane but also as essential bioactive factors regulating development and physiologic functions. Ceramide is a vital intermediate of sphingolipid metabolism, synthesized by de novo and salvage pathways, producing multiple types of sphingolipids and their metabolites. Although mutations in gene-encoding enzymes regulating sphingolipid synthesis and metabolism cause distinct diseases, an abnormal sphingolipid metabolism contributes to various pathologic conditions, including kidney diseases. Excessive accumulation of glycosphingolipids and promotion of the ceramide salvage and sphingosine-1-phosphate (S1P) pathways are found in the damaged kidney. Acceleration of the sphingosine kinase/S1P/S1P receptor (SphK/S1P/S1PR) axis plays a central role in deteriorating kidney functions. The SphK/S1P/S1PR signaling impairment is also found during pregnancy complications, such as preeclampsia and intrauterine growth restriction (IUGR). This mini-review discusses the current state of knowledge regarding the role of sphingolipid metabolism on kidney diseases, and the possible involvement of preeclampsia and IUGR conditions.Yokota, RodrigoBhunu, BenjaminToba, HiroeIntapad, Suttira2021-01-07T11:41:55-08:00doi:10.34067/KID.0006322020hwp:resource-id:kidney360;2/3/534American Society of NephrologyCopyright © 2021 by the American Society of NephrologyKidney360chronic kidney disease, basic science, fetal growth retardation, intrauterine growth restriction, IUGR, kidney diseases, preeclampsia, small for gestational age infant, sphingolipidsBasic Science for CliniciansBasic Science for Cliniciansother20212021-03-2510.34067/KID.00063220202641-76502021-01-07T11:41:55-08:002021-03-25Kidney360Basic Science for Clinicians23534541
- Proximal Tubular Oxidative Metabolism in Acute Kidney Injury and the Transition to CKDThe proximal tubule relies on oxidative mitochondrial metabolism to meet its energy needs and has limited capacity for glycolysis, which makes it uniquely susceptible to damage during AKI, especially after ischemia and anoxia. Under these conditions, mitochondrial ATP production is initially decreased by several mechanisms, including fatty acid–induced uncoupling and inhibition of respiration related to changes in the shape and volume of mitochondria. Glycolysis is initially insufficient as a source of ATP to protect the cells and mitochondrial function, but supplementation of tricarboxylic acid cycle intermediates augments anaerobic ATP production, and improves recovery of mitochondrial oxidative metabolism. Incomplete recovery is characterized by defects of respiratory enzymes and lipid metabolism. During the transition to CKD, tubular cells atrophy but maintain high expression of glycolytic enzymes, and there is decreased fatty acid oxidation. These metabolic changes may be amenable to a number of therapeutic interventions.10.34067/KID.0004772020Tue, 22 Dec 2020 09:45:36 GMT-08:00Proximal Tubular Oxidative Metabolism in Acute Kidney Injury and the Transition to CKDThe proximal tubule relies on oxidative mitochondrial metabolism to meet its energy needs and has limited capacity for glycolysis, which makes it uniquely susceptible to damage during AKI, especially after ischemia and anoxia. Under these conditions, mitochondrial ATP production is initially decreased by several mechanisms, including fatty acid–induced uncoupling and inhibition of respiration related to changes in the shape and volume of mitochondria. Glycolysis is initially insufficient as a source of ATP to protect the cells and mitochondrial function, but supplementation of tricarboxylic acid cycle intermediates augments anaerobic ATP production, and improves recovery of mitochondrial oxidative metabolism. Incomplete recovery is characterized by defects of respiratory enzymes and lipid metabolism. During the transition to CKD, tubular cells atrophy but maintain high expression of glycolytic enzymes, and there is decreased fatty acid oxidation. These metabolic changes may be amenable to a number of therapeutic interventions.Schaub, Jennifer A.Venkatachalam, Manjeri A.Weinberg, Joel M.2020-12-22T09:45:36-08:00doi:10.34067/KID.0004772020hwp:resource-id:kidney360;2/2/355American Society of NephrologyCopyright © 2021 by the American Society of NephrologyKidney360acute kidney injury and ICU nephrology, AKI, aTP, basic science, CKD, glycolysis, metabolism, mitochondria, tricarboxylic acid cycleBasic Science for CliniciansBasic Science for Cliniciansresearch-article20212021-02-2510.34067/KID.00047720202641-76502020-12-22T09:45:36-08:002021-02-25Kidney360Basic Science for Clinicians22355364
- The Relationship between APOL1 Structure and Function: Clinical ImplicationsCommon variants in the APOL1 gene are associated with an increased risk of nondiabetic kidney disease in individuals of African ancestry. Mechanisms by which APOL1 variants mediate kidney disease pathogenesis are not well understood. Amino acid changes resulting from the kidney disease–associated APOL1 variants alter the three-dimensional structure and conformational dynamics of the C-terminal α-helical domain of the protein, which can rationalize the functional consequences. Understanding the three-dimensional structure of the protein, with and without the risk variants, can provide insights into the pathogenesis of kidney diseases mediated by APOL1 variants.10.34067/KID.0002482020Wed, 04 Nov 2020 01:31:03 GMT-08:00The Relationship between APOL1 Structure and Function: Clinical ImplicationsCommon variants in the APOL1 gene are associated with an increased risk of nondiabetic kidney disease in individuals of African ancestry. Mechanisms by which APOL1 variants mediate kidney disease pathogenesis are not well understood. Amino acid changes resulting from the kidney disease–associated APOL1 variants alter the three-dimensional structure and conformational dynamics of the C-terminal α-helical domain of the protein, which can rationalize the functional consequences. Understanding the three-dimensional structure of the protein, with and without the risk variants, can provide insights into the pathogenesis of kidney diseases mediated by APOL1 variants.Madhavan, Sethu M.Buck, Matthias2020-11-04T13:31:03-08:00doi:10.34067/KID.0002482020hwp:resource-id:kidney360;2/1/134American Society of NephrologyCopyright © 2021 by the American Society of NephrologyKidney360chronic kidney disease, amino acids, APOL1, apolipoprotein L1, genetics, human APOL1 protein, kidney diseases, protein structure, Basic ScienceBasic Science for CliniciansBasic Science for Cliniciansother20212021-01-2810.34067/KID.00024820202641-76502020-11-04T13:31:03-08:002021-01-28Kidney360Basic Science for Clinicians21134140
- Shaping Up Mitochondria in Diabetic NephropathyMitochondrial medicine has experienced significant progress in recent years and is expected to grow significantly in the near future, yielding many opportunities to translate novel bench discoveries into clinical medicine. Multiple lines of evidence have linked mitochondrial dysfunction to a variety of metabolic diseases, including diabetic nephropathy (DN). Mitochondrial dysfunction presumably precedes the emergence of key histologic and biochemical features of DN, which provides the rationale to explore mitochondrial fitness as a novel therapeutic target in patients with DN. Ultimately, the success of mitochondrial medicine is dependent on a better understanding of the underlying biology of mitochondrial fitness and function. To this end, recent advances in mitochondrial biology have led to new understandings of the potential effect of mitochondrial dysfunction in a myriad of human pathologies. We have proposed that molecular mechanisms that modulate mitochondrial dynamics contribute to the alterations of mitochondrial fitness and progression of DN. In this comprehensive review, we highlight the possible effects of mitochondrial dysfunction in DN, with the hope that targeting specific mitochondrial signaling pathways may lead to the development of new drugs that mitigate DN progression. We will outline potential tools to improve mitochondrial fitness in DN as a novel therapeutic strategy. These emerging views suggest that the modulation of mitochondrial fitness could serve as a key target in ameliorating progression of kidney disease in patients with diabetes.10.34067/KID.0002352020Thu, 30 Jul 2020 10:36:47 GMT-07:00Shaping Up Mitochondria in Diabetic NephropathyMitochondrial medicine has experienced significant progress in recent years and is expected to grow significantly in the near future, yielding many opportunities to translate novel bench discoveries into clinical medicine. Multiple lines of evidence have linked mitochondrial dysfunction to a variety of metabolic diseases, including diabetic nephropathy (DN). Mitochondrial dysfunction presumably precedes the emergence of key histologic and biochemical features of DN, which provides the rationale to explore mitochondrial fitness as a novel therapeutic target in patients with DN. Ultimately, the success of mitochondrial medicine is dependent on a better understanding of the underlying biology of mitochondrial fitness and function. To this end, recent advances in mitochondrial biology have led to new understandings of the potential effect of mitochondrial dysfunction in a myriad of human pathologies. We have proposed that molecular mechanisms that modulate mitochondrial dynamics contribute to the alterations of mitochondrial fitness and progression of DN. In this comprehensive review, we highlight the possible effects of mitochondrial dysfunction in DN, with the hope that targeting specific mitochondrial signaling pathways may lead to the development of new drugs that mitigate DN progression. We will outline potential tools to improve mitochondrial fitness in DN as a novel therapeutic strategy. These emerging views suggest that the modulation of mitochondrial fitness could serve as a key target in ameliorating progression of kidney disease in patients with diabetes.Mise, KokiGalvan, Daniel L.Danesh, Farhad R.2020-07-30T10:36:47-07:00doi:10.34067/KID.0002352020hwp:resource-id:kidney360;1/9/982American Society of NephrologyCopyright © 2020 by the American Society of NephrologyKidney360diabetes and the kidney, diabetic nephropathy, ETC, mitochondria, mitochondrial biogenesis, mitochondrial complex activity, mitochondrial dynamics, mitochondrial fitness, mitophagy, OXPHOS, ROS, Basic ScienceBasic Science for CliniciansBasic Science for Cliniciansresearch-article20202020-09-2410.34067/KID.00023520202641-76502020-07-30T10:36:47-07:002020-09-24Kidney360Basic Science for Clinicians19982992
- Gadolinium-Based Contrast Agent Use, Their Safety, and Practice EvolutionGadolinium-based contrast agents (GBCAs) have provided much needed image enhancement in magnetic resonance imaging (MRI) important in the advancement of disease diagnosis and treatment. The paramagnetic properties of ionized gadolinium have facilitated these advancements, but ionized gadolinium carries toxicity risk. GBCAs were formulated with organic chelates designed to reduce these toxicity risks from unbound gadolinium ions. They were preferred over iodinated contrast used in computed tomography and considered safe for use. As their use expanded, the development of new diseases associated with their use (including nephrogenic systemic fibrosis) has drawn more attention and ultimately caution with their clinical administration in those with impaired renal function. Use of GBCAs in those with preserved renal function was considered to be safe. However, in this new era with emerging clinical and experimental evidence of brain gadolinium deposition in those with repeated exposure, these safety assumptions are once again brought into question. This review article aims to add new perspectives in thinking about the role of GBCA in current clinical use. The new information begs for further discussion and consideration of the risk-benefit ratio of use of GBCAs.10.34067/KID.0000272019Wed, 15 Apr 2020 01:24:45 GMT-07:00Gadolinium-Based Contrast Agent Use, Their Safety, and Practice EvolutionGadolinium-based contrast agents (GBCAs) have provided much needed image enhancement in magnetic resonance imaging (MRI) important in the advancement of disease diagnosis and treatment. The paramagnetic properties of ionized gadolinium have facilitated these advancements, but ionized gadolinium carries toxicity risk. GBCAs were formulated with organic chelates designed to reduce these toxicity risks from unbound gadolinium ions. They were preferred over iodinated contrast used in computed tomography and considered safe for use. As their use expanded, the development of new diseases associated with their use (including nephrogenic systemic fibrosis) has drawn more attention and ultimately caution with their clinical administration in those with impaired renal function. Use of GBCAs in those with preserved renal function was considered to be safe. However, in this new era with emerging clinical and experimental evidence of brain gadolinium deposition in those with repeated exposure, these safety assumptions are once again brought into question. This review article aims to add new perspectives in thinking about the role of GBCA in current clinical use. The new information begs for further discussion and consideration of the risk-benefit ratio of use of GBCAs.Do, CatherineDeAguero, JoshuaBrearley, AdrianTrejo, XochitlHoward, TamaraEscobar, G. PatriciaWagner, Brent2020-04-15T13:24:45-07:00doi:10.34067/KID.0000272019hwp:resource-id:kidney360;1/6/561American Society of NephrologyCopyright © 2020 by the American Society of NephrologyKidney360Chronic Kidney Disease, Contrast Media, Fibrosis, Gadolinium, Image Enhancement, Magnetic Resonance Imaging, Nephrogenic Fibrosing Dermopathy, Risk Assessment, Tomography, X-Ray Computed, Basic ScienceBasic Science for CliniciansBasic Science for Cliniciansresearch-article20202020-06-2510.34067/KID.00002720192641-76502020-04-15T13:24:45-07:002020-06-25Kidney360Basic Science for Clinicians16561568