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Cells May 2024Podocyte health is vital for maintaining proper glomerular filtration in the kidney. Interdigitating foot processes from podocytes form slit diaphragms which regulate... (Review)
Review
Podocyte health is vital for maintaining proper glomerular filtration in the kidney. Interdigitating foot processes from podocytes form slit diaphragms which regulate the filtration of molecules through size and charge selectivity. The abundance of lipid rafts, which are ordered membrane domains rich in cholesterol and sphingolipids, near the slit diaphragm highlights the importance of lipid metabolism in podocyte health. Emerging research shows the importance of sphingolipid metabolism to podocyte health through structural and signaling roles. Dysregulation in sphingolipid metabolism has been shown to cause podocyte injury and drive glomerular disease progression. In this review, we discuss the structure and metabolism of sphingolipids, as well as their role in proper podocyte function and how alterations in sphingolipid metabolism contributes to podocyte injury and drives glomerular disease progression.
Topics: Podocytes; Sphingolipids; Humans; Animals; Lipid Metabolism; Kidney Diseases; Membrane Microdomains
PubMed: 38891023
DOI: 10.3390/cells13110890 -
Nihon Rinsho Men'eki Gakkai Kaishi =... 2015It has recently become clear that initial glomerular injury affects glomerular visceral epithelial cells (also called as podocytes) as important target cells for... (Review)
Review
It has recently become clear that initial glomerular injury affects glomerular visceral epithelial cells (also called as podocytes) as important target cells for progression of chronic kidney disease (CKD) and end-stage kidney disease. Podocytes are injured in many human kidney diseases including minimal change disease, focal segmental glomerulosclerosis, diabetic nephropathy, membranous nephropathy and lupus nephritis. Podocytes are highly specialized epithelial cells that cover the outer layer of the glomerular basement membrane (GBM). Podocytes serve as the final barrier to urinary protein loss through the special formation and maintenance of foot-processes and an interposed slit-diaphragm. Chronic podocyte injury may cause podocyte detachment from the GBM, which leads to glomerulosclerosis. The elucidation of podocyte biology during the last 15 years has significantly improved our understanding of the pathophysiologic processes of proteinuria and glomerulosclerosis. In this review, we highlight some of new data including our recent findings for translating podocyte biology into new examinations and therapies for podocyte injury.
Topics: Glomerular Basement Membrane; Glomerulosclerosis, Focal Segmental; Humans; Nerve Tissue Proteins; Podocytes; Proteinuria; Receptor, Notch2; Renal Insufficiency, Chronic
PubMed: 25765686
DOI: 10.2177/jsci.38.26 -
Pediatric Nephrology (Berlin, Germany) Feb 2015In the past 20 years, multiple genetic mutations have been identified in patients with congenital nephrotic syndrome (CNS) and both familial and sporadic focal segmental... (Review)
Review
In the past 20 years, multiple genetic mutations have been identified in patients with congenital nephrotic syndrome (CNS) and both familial and sporadic focal segmental glomerulosclerosis (FSGS). Characterization of the genetic basis of CNS and FSGS has led to the recognition of the importance of podocyte injury to the development of glomerulosclerosis. Genetic mutations induce injury due to effects on the podocyte's structure, actin cytoskeleton, calcium signaling, and lysosomal and mitochondrial function. Transgenic animal studies have contributed to our understanding of podocyte pathobiology. Podocyte endoplasmic reticulum stress response, cell polarity, and autophagy play a role in maintenance of podocyte health. Further investigations related to the effects of genetic mutations on podocytes may identify new pathways for targeting therapeutics for nephrotic syndrome.
Topics: Animals; Humans; Nephrotic Syndrome; Podocytes; Proteinuria
PubMed: 24584664
DOI: 10.1007/s00467-014-2753-3 -
Archives of Endocrinology and Metabolism Jun 2023The incidence of diabetic nephropathy (DN) is gradually increasing worldwide. Podocyte injury, such as podocyte apoptosis and loss of the slit diaphragm (SD)-specific...
OBJECTIVE
The incidence of diabetic nephropathy (DN) is gradually increasing worldwide. Podocyte injury, such as podocyte apoptosis and loss of the slit diaphragm (SD)-specific markers are early pathogenic features of DN.
MATERIALS AND METHODS
The cultured mouse podocytes were separated into a high glucose-treated (HG, 30mM) group to mimic DN , a low glucose-treated (LG, 5mM) group as a control and HG+ angiotensin-(1-7)(Ang-(1-7)) and HG+Ang-(1-7) + D-Ala7-Ang-(1-7) (A779, Ang-(1-7)/Mas receptor antagonist) experimental groups. The Cell Counting Kit-8 (CCK-8) method and flow cytometry was used to detect podocyte activity and podocyte apoptosis respectively. The expression of angiotensin type 1 receptor (AT1R), Mas receptor (MasR) and podocyte-specific markers were examined by q-PCR and Western blot, respectively.
RESULTS
The results showed that the decrease in podocyte activity; the increase in podocyte apoptosis; the decreased mRNA and protein expression of nephrin, podocin, WT-1 and MasR; and the upregulated expression of AT1R induced by HG could be reversed by Ang-(1-7). However, these effects were blocked by A779. The possible mechanisms of the Ang-(1-7)-mediated effect depended on MasR. In addition, the protective effect of Ang-(1-7) on podocyte activity was dose-dependent and most obvious at 10 µM. A779 had the greatest antagonistic action against Ang-(1-7) at a concentration of 10 μM.
CONCLUSION
This study reveals that binding of Ang-(1-7) to its specific receptor MasR may counteract the effects of Ang II mediated by AT1R to significantly attenuate podocyte injury induced by high glucose. Ang-(1-7)/MasR targeting in podocytes may be a therapeutic approach to attenuate renal injury in DN.
Topics: Animals; Mice; Angiotensin II; Diabetic Nephropathies; Glucose; Podocytes
PubMed: 37364145
DOI: 10.20945/2359-3997000000643 -
Cells Jan 2021Fabry disease is a lysosomal storage disease with an X-linked heritage caused by absent or decreased activity of lysosomal enzymes named alpha-galactosidase A (α-gal...
Fabry disease is a lysosomal storage disease with an X-linked heritage caused by absent or decreased activity of lysosomal enzymes named alpha-galactosidase A (α-gal A). Among the various manifestations of Fabry disease, Fabry nephropathy significantly affects patients' morbidity and mortality. The cellular mechanisms of kidney damage have not been elusively described. Necroptosis is one of the programmed necrotic cell death pathways and is known to play many important roles in kidney injury. We investigated whether RIPK3, a protein phosphokinase with an important role in necroptosis, played a crucial role in the pathogenesis of Fabry nephropathy both in vitro and in vivo. The cell viability of podocytes decreased after lyso-Gb3 treatment in a dose-dependent manner, with increasing RIPK3 expression. Increased reactive oxygen species (ROS) generation after lyso-Gb3 treatment, which was alleviated by GSK'872 (a RIPK3 inhibitor), suggested a role of oxidative stress via a RIPK3-dependent pathway. Cytoskeleton rearrangement induced by lyso-Gb3 was normalized by the RIPK3 inhibitor. When mice were injected with lyso-Gb3, increased urine albuminuria, decreased podocyte counts in the glomeruli, and effaced foot processes were observed. Our results showed that lyso-Gb3 initiated albuminuria, a clinical manifestation of Fabry nephropathy, by podocyte loss and subsequent foot process effacement. These findings suggest a novel pathway in Fabry nephropathy.
Topics: Animals; Cell Death; Cytoskeleton; Female; Glycolipids; Injections, Intraperitoneal; Mice, Inbred C57BL; Models, Biological; Podocytes; Reactive Oxygen Species; Receptor-Interacting Protein Serine-Threonine Kinases; Sphingolipids; Mice
PubMed: 33513913
DOI: 10.3390/cells10020245 -
American Journal of Physiology. Renal... Feb 2009Glomerular diseases remain the leading cause of chronic and end-stage kidney disease. Significant advances in our understanding of human glomerular diseases have been... (Review)
Review
Glomerular diseases remain the leading cause of chronic and end-stage kidney disease. Significant advances in our understanding of human glomerular diseases have been enabled by the development and better characterization of animal models. Diseases of the glomerular epithelial cells (podocytes) account for the majority of proteinuric diseases. Rodents have been extensively used experimentally to better define mechanisms of disease induction and progression, as well as to identify potential targets and therapies. The development of podocyte-specific genetically modified mice has energized the research field to better understand which animal models are appropriate to study acquired podocyte diseases. In this review we discuss inducible experimental models of acquired nondiabetic podocyte diseases in rodents, namely, passive Heymann nephritis, puromycin aminonucleoside nephrosis, adriamycin nephrosis, liopolysaccharide, crescentic glomerulonephritis, and protein overload nephropathy models. Details are given on the model backgrounds, how to induce each model, the interpretations of the data, and the benefits and shortcomings of each. Genetic rodent models of podocyte injury are excluded.
Topics: Animals; Disease Models, Animal; Kidney Diseases; Mice; Podocytes; Rats
PubMed: 18784259
DOI: 10.1152/ajprenal.90421.2008 -
Cellular Physiology and Biochemistry :... 2019NLRP3 inflammasome activation has been reported to be an early mechanism responsible for glomerular inflammation and injury in obese mice. However, the precise mechanism...
BACKGROUND/AIMS
NLRP3 inflammasome activation has been reported to be an early mechanism responsible for glomerular inflammation and injury in obese mice. However, the precise mechanism of obesity-induced NLRP3 inflammasome activation remains unknown. The present study explored whether adipokine visfatin mediates obesity-induced NLRP3 inflammasome activation and consequent podocyte injury.
METHODS
Inflammasome formation and immunofluorescence expressions were quantified by confocal microscopy. Caspase-activity, IL-1β production and VEGF concentrations were measured by ELISA.
RESULTS
Confocal microscopic analysis showed that visfatin treatment increased the colocalization of Nlrp3 with Asc or Nlrp3 with caspase-1 in podocytes indicating the formation of NLRP3 inflammasomes. This visfatin-induced NLRP3 inflammasome formation was abolished by pretreatment of podocytes with Asc siRNA. Correspondingly, visfatin treatment significantly increased the caspase-1 activity and IL-1β production in podocytes, which was significantly attenuated by Asc siRNA transfection. Further RT-PCR and confocal microscopic analysis demonstrated that visfatin treatment significantly decreased the podocin expression (podocyte damage). Podocytes pretreatment with Asc siRNA or caspase-1 inhibitor, WEHD attenuated this visfatin-induced podocin reduction. Furthermore, Asc siRNA transfection was found to preserve podocyte morphology by maintaining the distinct arrangement of F-actin fibers normally lost in response to visfatin. It also prevented podocyte dysfunction by restoring visfatin-induced suppression of VEGF production and secretion.
CONCLUSION
Visfatin induces NLRP3 inflammasome activation in podocytes and thereby resulting in podocyte injury.
Topics: Adipokines; Animals; Cell Line; Inflammasomes; Inflammation; Interleukin-1beta; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Nicotinamide Phosphoribosyltransferase; Obesity; Podocytes; Vascular Endothelial Growth Factor A
PubMed: 31385664
DOI: 10.33594/000000143 -
Journal of the American Society of... Nov 2016This overview summarizes selected major developments over the last 40 years in understanding podocyte biology and its involvement in glomerular disease subjectively from... (Review)
Review
This overview summarizes selected major developments over the last 40 years in understanding podocyte biology and its involvement in glomerular disease subjectively from my perspective. Serendipity has played a major role in my contributions to investigative nephrology that range from basic mechanisms of immune deposit formation in experimental membranous nephropathy to the role of a microRNA in FSGS. This review emphasizes the importance of continuous reality checks of experimental results obtained in vitro or with genetically modified animals with human disease.
Topics: Animals; Awards and Prizes; Glomerulonephritis, Membranous; Humans; MicroRNAs; Podocytes
PubMed: 27324941
DOI: 10.1681/ASN.2016040490 -
Clinical Science (London, England :... Jun 2007The glomerular filtration barrier consists of the fenestrated endothelium, the glomerular basement membrane and the terminally differentiated visceral epithelial cells... (Review)
Review
The glomerular filtration barrier consists of the fenestrated endothelium, the glomerular basement membrane and the terminally differentiated visceral epithelial cells known as podocytes. It is now widely accepted that damage to, or originating within, the podocytes is a key event that initiates progression towards sclerosis in many glomerular diseases. A wide variety of strategies have been employed by investigators from many scientific disciplines to study the podocyte. Although invaluable insights have accrued from conventional approaches, including cell culture and biochemical-based methods, many renal researchers continue to rely upon the mouse to address the form and function of the podocyte. This review summarizes how genetic manipulation in the mouse has advanced our understanding of the podocyte in relation to the maintenance of the glomerular filtration barrier in health and disease.
Topics: Animals; Cell Adhesion Molecules; Gene Targeting; Glomerular Basement Membrane; Kidney Diseases; Membrane Proteins; Mice; Mice, Transgenic; Models, Animal; Podocytes
PubMed: 17291194
DOI: 10.1042/CS20060143 -
Biochimie May 2019Increased DAN protein (Grem1, Grem2, Grem3, Cerberus, NBL1, SOST, and USAG1) levels are often associated with severe disease-states in adult kidneys. Grem1, SOST, and...
BACKGROUND
Increased DAN protein (Grem1, Grem2, Grem3, Cerberus, NBL1, SOST, and USAG1) levels are often associated with severe disease-states in adult kidneys. Grem1, SOST, and USAG1 have been demonstrated to be upregulated and play a critical role in the progression of diabetic nephropathy (DN); however, the expression and the role of other DAN family members in DN have not been reported yet. In this study, we investigated the expression and the role of Grem2 in the development of renal lesions in mice with type 2 DN.
METHODS
Fourteen-week-old BTBR (a mouse model of type 2 diabetes mellitus) and control (BTBR, wild type) mice were evaluated for renal functional and structural biomarkers. Urine was collected for protein content assay, and renal tissues were harvested for molecular analysis with real-time PCR, Western blotting, and immunohistochemistry. In vitro studies, human podocytes were transfected with Grem2 plasmid and were evaluated for apoptosis (morphologic assay and Western blotting). To evaluate the Grem2-mediated downstream signaling, the phosphorylation status of Smad2/3 and Smad1/5/8 was assessed. To establish a causal relationship, the effect of SIS3 (an inhibitor for Samd2/3) and BMP-7 (an agonist for Smad1/5/8) was evaluated on Germ2-induced podocyte apoptosis.
RESULTS
BTBR mice showed elevated urinary protein levels. Renal tissues of BTBR mice showed an increased expression of Grem2; both glomerular and tubular cells displayed enhanced Grem2 expression. In vitro studies, high glucose increased Grem2 expression in cultured human podocytes, whereas, Grem2 silencing partially protected podocyte from high glucose-induced apoptosis. Overexpression of Grem2 in podocytes not only increased Bax/Bcl2 expression ratio but also promoted podocyte apoptosis; moreover, an overexpression of Grem2 increased the phosphorylation of Smad2/3 and decreased the phosphorylation of Smad1/5/8; furthermore, SIS3 and BMP-7 attenuated Grem2-induced podocyte apoptosis.
CONCLUSIONS
High glucose increases Grem2 expression in kidney cells. Grem2 mediates podocyte apoptosis through Smads.
Topics: Animals; Apoptosis; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glucose; Humans; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Obese; Phosphorylation; Podocytes; Signal Transduction; Sweetening Agents; Up-Regulation
PubMed: 30831151
DOI: 10.1016/j.biochi.2019.02.015