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American Journal of Physiology. Renal... Apr 2022The podocyte is an important component of the glomerular filtration barrier, and maintenance of the integrity of its highly specified structure and function is critical...
The podocyte is an important component of the glomerular filtration barrier, and maintenance of the integrity of its highly specified structure and function is critical for normal kidney function. Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) are two crucial effectors of the Hippo signaling pathway, and recent studies have shown that podocyte-specific YAP deletion causes podocyte apoptosis and the development of focal segmental glomerulosclerosis followed by progressive renal failure. In the present study, we investigated a potential role of the YAP paralog TAZ in podocytes. TAZ was found to be constitutively active in podocytes, and mice with podocyte-specific deletion of TAZ () developed proteinuria starting at 4 wk of age and had increased podocyte apoptosis. Using primary cultured podocytes or immortalized mouse podocytes from mice, we found that TAZ is a transcriptional activator for TEAD-dependent expression of synaptopodin, zonula occludens-1, and zonula occludens-2. This is the first study to determine that TAZ plays an important role in the maintenance of the structure and function of podocytes. Podocytes play an important role in maintaining the integrity of the structure and function of the kidney. We observed that mice with selective deletion of transcriptional coactivator with PDZ-binding motif (TAZ) in podocytes developed proteinuria. TAZ is constitutively active and critical for expression of synaptopodin, zonula occludens-1, and zonula occludens-2 in podocytes. The findings of this study implicate TAZ as an important mediator of podocyte structural integrity and provide further insights into the role of Hippo-Yes-associated protein/TAZ in podocyte biology.
Topics: Animals; Glomerulosclerosis, Focal Segmental; Kidney; Mice; Podocytes; Proteinuria; Transcription Factors
PubMed: 35157550
DOI: 10.1152/ajprenal.00426.2021 -
The Journal of Histochemistry and... Sep 2019Focal segmental glomerulosclerosis (FSGS) presents with scar in parts of some glomeruli and often progresses to global and diffuse glomerulosclerosis. Podocyte injury is... (Review)
Review
Focal segmental glomerulosclerosis (FSGS) presents with scar in parts of some glomeruli and often progresses to global and diffuse glomerulosclerosis. Podocyte injury is the initial target in primary FSGS, induced by a circulating factor. Several gene variants, for example, APOL1, are associated with increased susceptibility to FSGS. Primary FSGS may be due to genetic mutation in key podocyte genes. Increased work stress after loss of nephrons, epigenetic mechanisms, and various profibrotic pathways can contribute to progressive sclerosis, regardless of the initial injury. The progression of FSGS lesions also involves crosstalk between podocytes and other kidney cells, such as parietal epithelial cells, glomerular endothelial cells, and even tubular epithelial cells. New insights related to these mechanisms could potentially lead to new therapeutic strategies to prevent progression of FSGS.
Topics: Animals; Apolipoprotein L1; Cicatrix; Disease Progression; Endothelial Cells; Epigenesis, Genetic; Epithelial Cells; Glomerulosclerosis, Focal Segmental; Humans; Kidney Glomerulus; Kidney Tubules; Podocytes
PubMed: 31116068
DOI: 10.1369/0022155419850170 -
Cellular Physiology and Biochemistry :... Sep 2021Protein homeostasis strongly depends on the targeted and selective removal of unneeded or flawed proteins, of protein aggregates, and of damaged or excess organelles by... (Review)
Review
Protein homeostasis strongly depends on the targeted and selective removal of unneeded or flawed proteins, of protein aggregates, and of damaged or excess organelles by the two main intracellular degradative systems, namely the ubiquitin proteasomal system (UPS) and the autophagosomal lysosomal system. Despite representing completely distinct mechanisms of degradation, which underlie differing regulatory mechanisms, growing evidence suggests that the UPS and autophagy strongly interact especially in situations of overwhelming and impairment, and that both are involved in podocyte proteostasis and in the pathogenesis of podocyte injury. The differential impact of autophagy and the UPS on podocyte biology and on podocyte disease development and progression is not understood. Recent advances in understanding the role of the UPS and autophagy in podocyte biology are reviewed here.
Topics: Animals; Autophagosomes; Autophagy; Humans; Kidney Diseases; Lysosomes; Podocytes; Proteasome Endopeptidase Complex; Ubiquitin
PubMed: 34523304
DOI: 10.33594/000000432 -
Nutrients Oct 2023Nephrotic syndrome (NS) poses a number of nutritional and metabolic problems due to glomerulus injured podocytes, which are responsible for the loss of barrier function,...
Nephrotic syndrome (NS) poses a number of nutritional and metabolic problems due to glomerulus injured podocytes, which are responsible for the loss of barrier function, causing proteinuria, altered fluid and electrolyte balances, and hypoalbuminemia [...].
Topics: Humans; Nephrotic Syndrome; Podocytes; Proteinuria; Epithelial Cells
PubMed: 37960268
DOI: 10.3390/nu15214615 -
American Journal of Physiology. Renal... Mar 2021Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Besides glycemic and blood pressure control, environmental factors such as cigarette smoking...
Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Besides glycemic and blood pressure control, environmental factors such as cigarette smoking (CS) adversely affect the progression of DN. The effects of CS on DN progression have been attributed to combustion-generated molecules without consideration to the role of nicotine (NIC), responsible for the addictive properties of both CS and electronic cigarettes (ECs). Podocytes are essential to preserve the structure and function of the glomerular filtration barrier, and strong evidence indicates that early podocyte loss promotes DN progression. We performed experiments in human podocytes and in a mouse model of diabetes that develops nephropathy resembling human DN. We determined that NIC binding to podocytes in concentrations achieved with CS and ECs activated NADPH oxidase, which sets in motion a dysfunctional molecular network integrated by cyclooxygenase 2, known to induce podocyte injury; downregulation of AMP-activated protein kinase, important for maintaining cellular energy stores and antioxidation; and upregulation of CD36, which increased lipid uptake and promoted apoptosis. In diabetic mice, NIC increased proteinuria, a recognized marker of chronic kidney disease progression, accompanied by reduced glomerular podocyte synaptopodin, a crucial stabilizer of the podocyte cytoskeleton, and increased fibronectin expression. This novel study critically implicates NIC itself as a contributor to DN progression in CS and EC users. In this study, we demonstrate that nicotine increases the production of reactive oxygen species, increases cyclooxygenase-2 expression, and upregulates Cd36 while inducing downregulation of AMP-activated protein kinase. In vivo nicotine increases proteinuria and fibronectin expression in diabetic mice. This study demonstrates that effects of nicotine on podocytes are responsible, at least in part, for the deleterious effects of smoking in the progression of chronic kidney disease, including diabetic nephropathy.
Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Humans; Mice; Nicotine; Podocytes; Reactive Oxygen Species; Smoking
PubMed: 33459165
DOI: 10.1152/ajprenal.00194.2020 -
Metabolism: Clinical and Experimental Jan 2024Podocyte injury is considered as the most important early event contributing to diabetic kidney disease (DKD). Recent findings provide new insights into the roles of...
BACKGROUND AND AIMS
Podocyte injury is considered as the most important early event contributing to diabetic kidney disease (DKD). Recent findings provide new insights into the roles of lipids and lipid-modulating proteins as key determinants of podocyte function in health and kidney disease. CCDC92, a novel member of coiled-coil domain-containing protein family, was indicated relevant to lipid metabolism, coronary heart disease and type 2 diabetes. However, the expression pattern and role of CCDC92 in the kidney is not clear. This study was designed to elucidate the contribution of CCDC92 in the pathogenesis of DKD.
METHODS
Sections with a pathological diagnosis of different classes of DKD, including subjects with mild DKD (class II, n = 6), subjects with moderate DKD (class III, n = 6) or subjects with severe DKD (class IV, n = 6), and control samples (n = 12) were detected for the expression level of CCDC92 and lipid accumulation. Two types of diabetic mice model (db/db and HFD/STZ) in podocyte-specific Ccdc92 knockout background were generated to clarify the role of CCDC92 in podocyte lipotoxicity.
RESULTS
The level of CCDC92 was increased in renal biopsies sections from patients with DKD, which was correlated with eGFR and lipid accumulation in glomeruli. In animal studies, CCDC92 were also induced in the kidney from two independent diabetic models, especially in podocytes. Podocyte-specific deletion of Ccdc92 ameliorated podocyte injury and ectopic lipid deposition under diabetic condition. Mechanically, CCDC92 promoted podocyte lipotoxicity, at least in part through ABCA1 signaling-mediated lipid homeostasis.
CONCLUSION
Our studies demonstrates that CCDC92 acts as a novel regulator of lipid homeostasis to promote podocyte injury in DKD, suggesting that CCDC92 might be a potential biomarker of podocyte injury in DKD, and targeting CCDC92 may be an effective innovative therapeutic strategy for patients with DKD.
Topics: Animals; Humans; Mice; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Podocytes; Cytoskeletal Proteins; Lipid Metabolism
PubMed: 37952690
DOI: 10.1016/j.metabol.2023.155724 -
Biomolecules Mar 2022Podocytopathies are kidney diseases that are driven by podocyte injury with proteinuria and proteinuria-related symptoms as the main clinical presentations. Albeit... (Review)
Review
Podocytopathies are kidney diseases that are driven by podocyte injury with proteinuria and proteinuria-related symptoms as the main clinical presentations. Albeit podocytopathies are the major contributors to end-stage kidney disease, the underlying molecular mechanisms of podocyte injury remain to be elucidated. Mitochondrial oxidative stress is associated with kidney diseases, and increasing evidence suggests that oxidative stress plays a vital role in the pathogenesis of podocytopathies. Accumulating evidence has placed mitochondrial oxidative stress in the focus of cell death research. Excessive generated reactive oxygen species over antioxidant defense under pathological conditions lead to oxidative damage to cellular components and regulate cell death in the podocyte. Conversely, exogenous antioxidants can protect podocyte from cell death. This review provides an overview of the role of mitochondrial oxidative stress in podocytopathies and discusses its role in the cell death of the podocyte, aiming to identify the novel targets to improve the treatment of patients with podocytopathies.
Topics: Antioxidants; Cell Death; Female; Humans; Kidney Diseases; Male; Oxidative Stress; Podocytes; Proteinuria; Reactive Oxygen Species
PubMed: 35327595
DOI: 10.3390/biom12030403 -
Frontiers in Immunology 2021The discovery of anti-podocyte antibodies in primary membranous nephropathy (MN) has revolutionized our approach toward the diagnosis and treatment of this disease.... (Review)
Review
The discovery of anti-podocyte antibodies in primary membranous nephropathy (MN) has revolutionized our approach toward the diagnosis and treatment of this disease. Evaluation of serum levels of anti-podocyte antibodies paved the way for non-invasive diagnosis and helped distinguish between primary and secondary MN although the relationship between anti-podocyte antibodies and cancer remains to be elucidated. Serum levels of anti-PLA2R antibodies directed against the major podocyte autoantigen are related to MN activity and the decrease in serum levels of anti-PLA2R antibodies in response to treatment (immunologic remission) also serves as an early indicator of the later putative proteinuric remission, enabling personalization of the treatment. The serum levels of anti-podocyte antibodies also enable the prediction of renal outcomes in terms of both remission and the risk of progression to end-stage renal disease. The positivity of anti-PLA2R antibodies before renal transplantation is associated with the risk of recurrence of MN. It remains to be established if all these relations observed in patients with anti-PLA2R antibodies are also valid for expanding spectrum of antibodies directed against recently discovered minor antigens (e.g., THSD7A, NELL-1, semaphorin 3B).
Topics: Animals; Autoantibodies; Autoantigens; Autoimmunity; Combined Modality Therapy; Disease Management; Disease Susceptibility; Glomerulonephritis, Membranous; Humans; Kidney Glomerulus; Molecular Diagnostic Techniques; Podocytes; Receptors, Phospholipase A2
PubMed: 33828546
DOI: 10.3389/fimmu.2021.593288 -
International Journal of Molecular... Feb 2020Podocytes are visceral epithelial cells covering the outer surface of glomerular capillaries in the kidney. Blood is filtered through the slit diaphragm of podocytes to... (Review)
Review
Podocytes are visceral epithelial cells covering the outer surface of glomerular capillaries in the kidney. Blood is filtered through the slit diaphragm of podocytes to form urine. The functional and structural integrity of podocytes is essential for the normal function of the kidney. As a membrane-bound organelle, lysosomes are responsible for the degradation of molecules via hydrolytic enzymes. In addition to its degradative properties, recent studies have revealed that lysosomes may serve as a platform mediating cellular signaling in different types of cells. In the last decade, increasing evidence has revealed that the normal function of the lysosome is important for the maintenance of podocyte homeostasis. Podocytes have no ability to proliferate under most pathological conditions; therefore, lysosome-dependent autophagic flux is critical for podocyte survival. In addition, new insights into the pathogenic role of lysosome and associated signaling in podocyte injury and chronic kidney disease have recently emerged. Targeting lysosomal functions or signaling pathways are considered potential therapeutic strategies for some chronic glomerular diseases. This review briefly summarizes current evidence demonstrating the regulation of lysosomal function and signaling mechanisms as well as the canonical and noncanonical roles of podocyte lysosome dysfunction in the development of chronic glomerular diseases and associated therapeutic strategies.
Topics: Animals; Autophagy; Diabetic Nephropathies; Glomerulonephritis; Humans; Lipid Metabolism; Lysosomes; Podocytes
PubMed: 32106480
DOI: 10.3390/ijms21051559 -
Molecular Medicine Reports Nov 2023Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder caused by the loss of tolerance to endogenous nuclear antigens such as double‑stranded DNA,... (Review)
Review
Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder caused by the loss of tolerance to endogenous nuclear antigens such as double‑stranded DNA, leading to the proliferation of T cells and subsequent activation of B cells, which results in serious organ damage and life‑threatening complications such as lupus nephritis. Lupus nephritis (LN) develops as a frequent complication of SLE, accounting for >60% of SLE cases, and is characterized by proteinuria and heterogeneous histopathological findings. Glomerular injury serves a role in proteinuria as podocyte damage is the leading contributor. Numerous studies have reported that podocytes are involved in the immune response that promotes LN progression. In LN, immune complex deposition stimulates dendritic cells to secrete inflammatory cytokines that activate T cells and B cells. B cells secrete autoantibodies that attack and damage the renal podocytes, leading to renal podocyte injury. The injured podocytes trigger inflammatory cells through the expression of toll‑like receptors and trigger T cells through major histocompatibility complexes and CD86, thereby participating in the local immune response and the exacerbation of podocyte injury. Based on the existing literature, the present review summarizes the research progress of podocytes in LN under the local immune microenvironment of the kidney, explores the mechanism of podocyte injury under the immune microenvironment, and evaluates podocytes as a potential therapeutic target for LN.
Topics: Humans; Lupus Nephritis; Podocytes; Kidney; Lupus Erythematosus, Systemic; Proteinuria
PubMed: 37711069
DOI: 10.3892/mmr.2023.13091