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Nature Reviews. Disease Primers Aug 2020Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants... (Review)
Review
Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants in >50 podocyte-expressed genes, syndromal non-podocyte-specific genes and phenocopies with other underlying genetic abnormalities cause podocytopathies associated with steroid-resistant nephrotic syndrome or severe proteinuria. A variety of genetic variants likely contribute to disease development. Among genes with non-Mendelian inheritance, variants in APOL1 have the largest effect size. In addition to genetic variants, environmental triggers such as immune-related, infection-related, toxic and haemodynamic factors and obesity are also important causes of podocyte injury and frequently combine to cause various degrees of proteinuria in children and adults. Typical manifestations on kidney biopsy are minimal change lesions and focal segmental glomerulosclerosis lesions. Standard treatment for primary podocytopathies manifesting with focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs; individuals not responding with a resolution of proteinuria have a poor renal prognosis. Renin-angiotensin system antagonists help to control proteinuria and slow the progression of fibrosis. Symptomatic management may include the use of diuretics, statins, infection prophylaxis and anticoagulation. This Primer discusses a shift in paradigm from patient stratification based on kidney biopsy findings towards personalized management based on clinical, morphological and genetic data as well as pathophysiological understanding.
Topics: Humans; Kidney; Nephrotic Syndrome; Podocytes; Prevalence; Proteinuria
PubMed: 32792490
DOI: 10.1038/s41572-020-0196-7 -
Kidney International Jun 2016Podocytes maintain the glomerular filtration barrier, and the stability of this barrier depends on their highly differentiated postmitotic phenotype, which also defines... (Review)
Review
Podocytes maintain the glomerular filtration barrier, and the stability of this barrier depends on their highly differentiated postmitotic phenotype, which also defines the particular vulnerability of the glomerulus. Recent podocyte biology and gene disruption studies in vivo indicate a causal relationship between abnormalities of single podocyte molecules and proteinuria and glomerulosclerosis. Podocytes live under various stresses and pathological stimuli. They adapt to maintain homeostasis, but excessive stress leads to maladaptation with complex biological changes including loss of integrity and dysregulation of cellular metabolism. Podocyte injury causes proteinuria and detachment from the glomerular basement membrane. In addition to "sick" podocytes and their detachment, our understanding of glomerular responses following podocyte loss needs to address the pathways from podocyte injury to sclerosis. Studies have found a variety of glomerular responses to podocyte dysfunction in vivo, such as disruption of podocyte-endothelial cross talk and activation of podocyte-parietal cell interactions, all of which help us to understand the complex scenario of podocyte injury and its consequences. This review focuses on the cellular aspects of podocyte dysfunction and the adaptive or maladaptive glomerular responses to podocyte injury that lead to its major consequence, glomerulosclerosis.
Topics: Apoptosis; Bowman Capsule; Cell Communication; Cell Differentiation; Endothelial Cells; Glomerular Basement Membrane; Glomerulosclerosis, Focal Segmental; Humans; Oxidative Stress; Podocytes; Proteinuria; Sclerosis; Stress, Mechanical
PubMed: 27165817
DOI: 10.1016/j.kint.2016.01.012 -
Cell Metabolism Dec 2020Lipid accumulation in podocytes is a major determinant of diabetic kidney disease (DKD) and identification of potential therapeutic targets by mediating podocyte lipid...
Lipid accumulation in podocytes is a major determinant of diabetic kidney disease (DKD) and identification of potential therapeutic targets by mediating podocyte lipid metabolism has clinical importance. This study was to elucidate the role of JAML (junctional adhesion molecule-like protein) in the pathogenesis of DKD. We first confirmed the expression of JAML in podocytes and found that podocyte-specific deletion of Jaml ameliorated podocyte injury and proteinuria in two different models of diabetic mice. We further demonstrated a novel role of JAML in regulating podocyte lipid metabolism through SIRT1-mediated SREBP1 signaling. Similar results were also found in mice with adriamycin-induced nephropathy. Importantly, we observed a higher expression of JAML in glomeruli from subjects with DKD and other types of proteinuric kidney diseases, and the level of JAML was correlated with lipid accumulation and glomerular filtration rate, suggesting that JAML may be an attractive therapeutic target for proteinuric kidney disease.
Topics: Adult; Aged; Animals; Cell Adhesion Molecules; Cell Line; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Female; Humans; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Middle Aged; Podocytes; Rats; Young Adult
PubMed: 33186558
DOI: 10.1016/j.cmet.2020.10.019 -
American Journal of Nephrology 2018Podocyte biology is a developing science that promises to help improve understanding of the mechanistic nature of multiple diseases associated with proteinuria.... (Review)
Review
BACKGROUND
Podocyte biology is a developing science that promises to help improve understanding of the mechanistic nature of multiple diseases associated with proteinuria. Proteinuria in nephrotic syndrome has been linked to mechanistic dysfunctions in the renal glomerulus involving the function of podocyte epithelial cells, including podocyte foot process effacement.
SUMMARY
Developments in imaging technology are improving knowledge of the detailed structure of the human renal glomerulus and cortex. Podocyte foot processes attach themselves to the glomerular capillaries at the glomerular basement membrane (GBM) forming intercellular junctions that form slit diaphragm filtration barriers that help maintain normal renal function. Damage in this area has been implicated in glomerular disease. Injured podocytes undergo effacement whereby they lose their structure and spread out, leading to a reduction in filtration barrier function. Effacement is typically associated with the presence of proteinuria in focal segmental glomerulosclerosis, minimal change disease, and diabetes. It is thought to be due to a breakdown in the actin cytoskeleton of the foot processes, complex contractile apparatuses that allow podocytes to dynamically reorganize according to changes in filtration requirements. The process of podocyte depletion correlates with the development of glomerular sclerosis and chronic kidney disease. Focal adhesion complexes that interact with the underlying GBM bind the podocytes within the glomerular structure and prevent their detachment. Key Messages: Knowledge of glomerular podocyte biology is helping to advance our understanding of the science and mechanics of the glomerular filtering process, opening the way to a variety of new potential applications for clinical targeting.
Topics: Actins; Humans; Membrane Proteins; Nephrotic Syndrome; Podocytes; Proteinuria
PubMed: 29852492
DOI: 10.1159/000481633 -
Journal of the American Society of... Nov 2021The effects of healthy aging on the kidney, and how these effects intersect with superimposed diseases, are highly relevant in the context of the population's increasing... (Review)
Review
The effects of healthy aging on the kidney, and how these effects intersect with superimposed diseases, are highly relevant in the context of the population's increasing longevity. Age-associated changes to podocytes, which are terminally differentiated glomerular epithelial cells, adversely affect kidney health. This review discusses the molecular and cellular mechanisms underlying podocyte aging, how these mechanisms might be augmented by disease in the aged kidney, and approaches to mitigate progressive damage to podocytes. Furthermore, we address how biologic pathways such as those associated with cellular growth confound aging in humans and rodents.
Topics: Adult; Aged; Aging; Animals; Autophagy; Caloric Restriction; Cell Cycle; Cell Shape; Cells, Cultured; Cellular Senescence; DNA Damage; Female; Gene Expression; Humans; Inflammasomes; Kidney Glomerulus; Male; Mice; Middle Aged; Mitochondria; Models, Animal; Oligopeptides; Oxidative Stress; Podocytes; Rats; Regulated Cell Death; Sirtuins; Species Specificity; Young Adult
PubMed: 34716239
DOI: 10.1681/ASN.2021050614 -
The Journal of Clinical Investigation Oct 2020Using the Nephrotic Syndrome Study Network Consortium data set and other publicly available transcriptomic data sets, we identified retinoic acid receptor responder...
Using the Nephrotic Syndrome Study Network Consortium data set and other publicly available transcriptomic data sets, we identified retinoic acid receptor responder protein 1 (RARRES1) as a gene whose expression positively correlated with renal function decline in human glomerular disease. The glomerular expression of RARRES1, which is largely restricted to podocytes, increased in focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). TNF-α was a potent inducer of RARRES1 expression in cultured podocytes, and transcriptomic analysis showed the enrichment of cell death pathway genes with RARRES1 overexpression. The overexpression of RARRES1 indeed induced podocyte apoptosis in vitro. Notably, this effect was dependent on its cleavage in the extracellular domain, as the mutation of its cleavage site abolished the apoptotic effect. Mechanistically, the soluble RARRES1 was endocytosed and interacted with and inhibited RIO kinase 1 (RIOK1), resulting in p53 activation and podocyte apoptosis. In mice, podocyte-specific overexpression of RARRES1 resulted in marked glomerular injury and albuminuria, while the overexpression of RARRES1 cleavage mutant had no effect. Conversely, podocyte-specific knockdown of Rarres1 in mice ameliorated glomerular injury in the setting of adriamycin-induced nephropathy. Our study demonstrates an important role and the mechanism of RARRES1 in podocyte injury in glomerular disease.
Topics: Animals; Apoptosis; Cells, Cultured; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Gene Knockdown Techniques; Glomerulosclerosis, Focal Segmental; Humans; Kidney Glomerulus; Membrane Proteins; Mice; Mice, Transgenic; Mutant Proteins; Podocytes; RNA, Messenger; Signal Transduction; Solubility; Tumor Necrosis Factor-alpha; Up-Regulation
PubMed: 32634130
DOI: 10.1172/JCI140155 -
Cell Death & Disease Sep 2021Podocytes are known to play a determining role in the progression of proteinuric kidney disease. N-methyladenosine (m6A), as the most abundant chemical modification in...
Podocytes are known to play a determining role in the progression of proteinuric kidney disease. N-methyladenosine (m6A), as the most abundant chemical modification in eukaryotic mRNA, has been reported to participate in various pathological processes. However, its role in podocyte injury remains unclear. In this study, we observed the elevated m6A RNA levels and the most upregulated METTL14 expression in kidneys of mice with adriamycin (ADR) and diabetic nephropathy. METTL14 was also evidently increased in renal biopsy samples from patients with focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy and in cultured human podocytes with ADR or advanced glycation end product (AGE) treatment in vitro. Functionally, we generated mice with podocyte-specific METTL14 deletion, and identified METTL14 knockout in podocytes improved glomerular function and alleviated podocyte injury, characterized by activation of autophagy and inhibition of apoptosis and inflammation, in mice with ADR nephropathy. Similar to the results in vivo, knockdown of METTL14 facilitated autophagy and alleviated apoptosis and inflammation in podocytes under ADR or AGE condition in vitro. Mechanically, we identified METTL14 knockdown upregulated the level of Sirt1, a well-known protective deacetylase in proteinuric kidney diseases, in podocytes with ADR or AGE treatment. The results of MeRIP-qPCR and dual-luciferase reporter assay indicated METTL14 promoted Sirt1 mRNA m6A modification and degradation in injured podocytes. Our findings suggest METTL14-dependent RNA m6A modification contributes to podocyte injury through posttranscriptional regulation of Sirt1 mRNA, which provide a potential approach for the diagnosis and treatment of podocytopathies.
Topics: Adenosine; Animals; Apoptosis; Autophagy; Cytoprotection; Diabetic Nephropathies; Disease Progression; Down-Regulation; Doxorubicin; Gene Silencing; Glycation End Products, Advanced; Inflammation; Male; Methyltransferases; Mice, Inbred C57BL; Models, Biological; Podocytes; RNA, Messenger; Sirtuin 1; Up-Regulation; Mice
PubMed: 34580283
DOI: 10.1038/s41419-021-04156-y -
Kidney360 Dec 2023As the population in many industrial countries is aging, the risk, incidence, and prevalence of CKD increases. In the kidney, advancing age results in a progressive... (Review)
Review
As the population in many industrial countries is aging, the risk, incidence, and prevalence of CKD increases. In the kidney, advancing age results in a progressive decrease in nephron number and an increase in glomerulosclerosis. In this review, we focus on the effect of aging on glomerular podocytes, the post-mitotic epithelial cells critical for the normal integrity and function of the glomerular filtration barrier. The podocytes undergo senescence and transition to a senescence-associated secretory phenotype typified by the production and secretion of inflammatory cytokines that can influence neighboring glomerular cells by paracrine signaling. In addition to senescence, the aging podocyte phenotype is characterized by ultrastructural and functional changes; hypertrophy; cellular, oxidative, and endoplasmic reticulum stress; reduced autophagy; and increased expression of aging genes. This results in a reduced podocyte health span and a shortened life span. Importantly, these changes in the pathways/processes characteristic of healthy podocyte aging are also often similar to pathways in the disease-induced injured podocyte. Finally, the better understanding of podocyte aging and senescence opens therapeutic options to slow the rate of podocyte aging and promote kidney health.
Topics: Humans; Podocytes; Aging; Kidney Glomerulus; Kidney Diseases; Epithelial Cells
PubMed: 37950369
DOI: 10.34067/KID.0000000000000284 -
International Journal of Biological... 2019Previous studies have shown that mitochondrial dysfunction plays an important role in high- glucose(HG)-induced podocyte injury and thus contributes to the progression...
Previous studies have shown that mitochondrial dysfunction plays an important role in high- glucose(HG)-induced podocyte injury and thus contributes to the progression of diabetic nephropathy(DN). The histone deacetylase Sirtuin6 (Sirt6) has been revealed to have an essential role in the regulation of mitochondrial function in skeletal muscle and cardiomyocytes. However, its specific role in mitochondrial homeostasis in podocytes is undetermined. Here, we aimeds to explore the physiological function of Sirt6 in podocyte mitochondria and apoptosis under HG conditions and explore the possible mechanism. Herein, we observed that Sirt6-WT-1 colocalization was suppressed in the glomeruli of patients with DN. In addition, diabetic mice exhibited reduced Sirt6 expression and AMP kinase (AMPK) dephosphorylation accompanied by mitochondrial morphological abnormalities. , podocytes exposed to HG presented with mitochondrial morphological alterations and podocyte apoptosis accompanied by Sirt6 and p-AMPK downregulation. In addition, HG promoted a decrease in mitochondrial number and an increase in mitochondrial superoxide production as well as a decreased mitochondrial membrane potential. ROS production was also increased in HG-treated podocytes. Conversely, all these mitochondrial defects induced by HG were significantly alleviated by Sirt6 plasmid transfection. Sirt6 overexpression simultaneously alleviated HG-induced podocyte apoptosis and oxidative stress, as well as increased AMPK phosphorylation. Increased levels of H3K9ac and H3K56ac induced by HG were attenuated in podocytes transfected with Sirt6 plasmids. Therefore, these results elucidated that Sirt6 protects mitochondria of podocytes and exerts anti-apoptotic effects via activating AMPK pathway. The present findings provide key insights into the pivotal role of mitochondria regulation by SIRT6 in its protective effects on podocytes.
Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Glucose; Immunohistochemistry; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mitochondria; Phosphorylation; Podocytes; Sirtuins; Superoxides
PubMed: 30745856
DOI: 10.7150/ijbs.29323 -
Biomedicine & Pharmacotherapy =... Dec 2022Renal injury and the development of albuminuria are tightly connected with the loss of podocytes. Podocyte damages cause proteinuric renal diseases since podocyte foot... (Review)
Review
Renal injury and the development of albuminuria are tightly connected with the loss of podocytes. Podocyte damages cause proteinuric renal diseases since podocyte foot processes (FP) and their interposed slit diaphragms (SD) are the final barriers against protein loss. Podocyte effacement and the resultant deterioration of podocyte SD integrity that involve the active rearrangement of the podocyte actin cytoskeleton is a chief mechanism of proteinuric kidney diseases. The progress of these injuries can eventually lead to cell detachment and death. Due to the prominence of the actin cytoskeleton in maintaining glomerular filtration, the assessment of the molecular design and regulation of actin is a central target of podocyte research. In the current review, a comprehensive summary of the actin cytoskeleton, its constituents, and regulatory signaling pathways has been provided. Since actin-regulated cell plasticity is a crucial feature of normal podocyte function, and deteriorations in its dynamics seem to directly affect podocyte morphology and glomerular permeability, this review discusses cascades that regulate actin polymerization in podocytes.
Topics: Actins; Actin Cytoskeleton; Podocytes; Kidney Glomerulus; Intercellular Junctions
PubMed: 36411613
DOI: 10.1016/j.biopha.2022.113920