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BioMed Research International 2013Proteinuria is an independent risk factor for end-stage renal disease (ESRD) (Shankland, 2006). Recent studies highlighted the mechanisms of podocyte injury and... (Review)
Review
Proteinuria is an independent risk factor for end-stage renal disease (ESRD) (Shankland, 2006). Recent studies highlighted the mechanisms of podocyte injury and implications for potential treatment strategies in proteinuric kidney diseases (Zhang et al., 2012). Reactive oxygen species (ROS) are cellular signals which are closely associated with the development and progression of glomerular sclerosis. NADPH oxidase is a district enzymatic source of cellular ROS production and prominently expressed in podocytes (Zhang et al., 2010). In the last decade, it has become evident that NADPH oxidase-derived ROS overproduction is a key trigger of podocyte injury, such as renin-angiotensin-aldosterone system activation (Whaley-Connell et al., 2006), epithelial-to-mesenchymal transition (Zhang et al., 2011), and inflammatory priming (Abais et al., 2013). This review focuses on the mechanism of NADPH oxidase-mediated ROS in podocyte injury under different pathophysiological conditions. In addition, we also reviewed the therapeutic perspectives of NADPH oxidase in kidney diseases related to podocyte injury.
Topics: Animals; Humans; NADPH Oxidases; Podocytes; Proteinuria; Reactive Oxygen Species; Renin-Angiotensin System
PubMed: 24319690
DOI: 10.1155/2013/839761 -
Molecular and Cellular Endocrinology Aug 2019Diabetic nephropathy (DN) is a progressive disease, the main pathogeny of which is podocyte injury. As a calcium-dependent serine/threonine protein kinase involved in...
Diabetic nephropathy (DN) is a progressive disease, the main pathogeny of which is podocyte injury. As a calcium-dependent serine/threonine protein kinase involved in podocyte injury, protein kinase C isoform α (PKCα) was reported to regulate the phosphorylation of p66SHC. However, the role of PKCα/p66SHC in DN remains unknown. Klotho, an anti-aging protein with critical roles in protecting kidney, is expressed predominantly in the kidney and secreted in the blood. Nonetheless, the mechanism underlying amelioration of podocyte injury by Klotho in DN remains unclear. Our data showed that Klotho was decreased in STZ-treated mice and was further declined in diabetic KL ± mice. As expected, Klotho deficiency aggravated diabetes-induced proteinuria and podocyte injury, accompanied by the activation of PKCα and p66SHC. In contrast, overexpression of Klotho partially ameliorated PKCα/p66SHC-mediated podocyte injury and proteinuria. In addition, in vitro experiments showed that activation of PKCα and subsequently increased intracellular reactive oxygen species (ROS) was involved in podocytic apoptosis induced by high glucose (HG), which could be partially reversed by Klotho. Hence, we conclude that Klotho might inhibit PKCα/p66SHC-mediated podocyte injury in diabetic nephropathy.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Glucuronidase; Klotho Proteins; Male; Mice, Inbred C57BL; Phenotype; Podocytes; Protein Kinase C-alpha; Proteinuria; Src Homology 2 Domain-Containing, Transforming Protein 1; Streptozocin
PubMed: 31207271
DOI: 10.1016/j.mce.2019.110490 -
Nephrology (Carlton, Vic.) Aug 2006Although the role of glomerular basement membrane has been emphasised as the barrier for retaining plasma proteins in the past three decades, some recent studies have... (Review)
Review
Although the role of glomerular basement membrane has been emphasised as the barrier for retaining plasma proteins in the past three decades, some recent studies have demonstrated that the slit diaphragm of the glomerular epithelial cell (podocyte) is the structure likely to be the barrier in the glomerular capillary wall. Nephrin and podocin were identified as gene products mutated in Finnish-type congenital nephrotic syndrome and autosomal recessive steroid-resistant nephrotic syndrome, respectively. Nephrin s located at the outer leaflet of plasma membranes of the slit diaphragm. Podocin is reported to have an interaction with nephrin. The anti-nephrin antibody is capable of inducing massive proteinuria, which indicates that nephrin is a key functional molecule in the slit diaphragm. The expression of nephrin and podocin was reduced in glomeruli of minimal change nephrotic syndrome, which suggested that the altered expression of these molecules contributes to the development of proteinuria also in acquired diseases. Some recent studies demonstrated that CD2-associated protein (CD2AP) is also a functional molecule in the slit diaphragm, and its expression is altered in membranous nephropathy. These observations suggested that alteration of the molecular arrangement in the slit diaphragm is involved in the development of proteinuria in several kinds of glomerular diseases.
Topics: Animals; Humans; Podocytes
PubMed: 16889564
DOI: 10.1111/j.1440-1797.2006.00583.x -
Kidney & Blood Pressure Research 2010Injured podocytes proliferate in cellular focal segmental glomerulosclerosis (FSGS), collapsing FSGS and crescentic glomerulonephritis, where TGF-beta(1) is... (Review)
Review
Injured podocytes proliferate in cellular focal segmental glomerulosclerosis (FSGS), collapsing FSGS and crescentic glomerulonephritis, where TGF-beta(1) is overexpressed in hyperplastic podocytes. Yet effects of podocyte TGF-beta on podocyte growth and development of glomerulosclerosis have not been clearly defined. TGF-beta activates Smads, Ras/extracellular signal-regulated kinase (ERK) and phosphatidyl inositol-3-kinase (PI3K) pathways in podocytes, of which the major TGF-beta/Smad signaling pathway appears to override the minor TGF-beta-induced Ras/ERK/PI3K pathways. We provide evidence that increasedTGF-beta/Smad signaling activity by hyperplastic podocytes may lead to mesangial cell matrix overproduction and eventually to podocyte apoptosis and/or detachment, culminating in the development of glomerulosclerosis. In this regard, TGF-beta, which is overexpressed by hyperplastic podocytes, may play an important role for the cellular and collapsing variants of FSGS to evolve into the classic FSGS pattern. In contrast, podocyte proliferation that is induced by Ras/ERK signaling activity in proliferative podocyte diseases seems to be mostly independent of TGF-beta(1) activity. Collectively, these data bring new insights into our understanding of the overexpression of TGF-beta in hyperplastic podocytes in progressive glomerular diseases.
Topics: Glomerulosclerosis, Focal Segmental; Humans; Podocytes; Signal Transduction; Transforming Growth Factor beta
PubMed: 20185928
DOI: 10.1159/000285844 -
Nephron. Experimental Nephrology 2007The glomerular visceral epithelial cell, or podocyte, is a highly specialized and terminally differentiated cell that is fundamental to the integrity of the glomerular... (Review)
Review
The glomerular visceral epithelial cell, or podocyte, is a highly specialized and terminally differentiated cell that is fundamental to the integrity of the glomerular filtration barrier and functions to prevent urinary protein leakage and to oppose intracapillary hydrostatic pressure. Common to many human kidney diseases and experimental animal models is a strong association between podocyte injury and the development of progressive kidney disease. Studies have shown that a decline in podocyte number strongly correlates with, and likely underlies, proteinuria and the progression to glomerulosclerosis. Maintenance of podocyte differentiation, essential to its normal structure and function, is challenged in the setting of glomerular injury, with very divergent outcomes dependent upon the inciting injury. In response to injury, podocytes may undergo several cell fates, including proliferation, de-differentiation, hypertrophy, apoptosis, or necrosis. Common to these potential outcomes of renal injury is their ultimate regulation at the level of the cell cycle. Positive regulators (cyclins and cyclin-dependent kinases) and negative regulators (cyclin-dependent kinase inhibitors) coordinate the cell cycle. There is now a large body of literature confirming the importance of cell cycle regulatory proteins in the cellular response to injury. Emerging lessons from mouse knockout experiments highlight that the cell cycle machinery operates differently in distinct cell types. Recent studies focusing on the roles of cell cycle regulatory proteins specifically in podocytes have provided important clues on how these proteins operate to constrain cell proliferation and preserve differentiation in health, and how they modulate the dysregulated phenotype in diseased states. In disease, both a failure to regenerate lost podocytes and an inappropriate proliferative response can have profound consequences for glomerular structure and function. Here, we will review the latest advances in understanding the roles of cell cycle regulatory proteins in diseases of the podocyte.
Topics: Animals; Cell Cycle; Cell Cycle Proteins; Cyclins; Humans; Kidney Diseases; Models, Biological; Podocytes
PubMed: 17570940
DOI: 10.1159/000101793 -
Biochemical and Biophysical Research... Jun 2021Klotho deficiency was observed in virtually all kinds of kidney disease and is thought to play a critical role in podocyte injury. However, the underline mechanisms...
Klotho deficiency was observed in virtually all kinds of kidney disease and is thought to play a critical role in podocyte injury. However, the underline mechanisms involved in podocyte injury remain unknown. miRNAs have diverse regulatory roles, and miR-30 family members were essential for podocyte homeostasis. Our study revealed that Klotho and miR-30s were downregulated in PAN-treated podocytes. The ectopic expression of Klotho ameliorates PAN induced podocyte apoptosis through upregulating miR-30a and downregulating Ppp3ca, Ppp3cb, Ppp3r1, and Nfact3 expression, which are the known targets of miR-30s. We also found that Klotho regulates TRPC6 via miR-30a to activate calcium/calcineurin signaling. Further, glucocorticoid (Dexamethasone, DEX) was found to sustain Klotho and miR-30a levels during PAN treatment in vitro. Eventually, in rats, PAN treatment substantially downregulated Klotho and miR-30a levels, lead to podocyte injury and increased proteinuria. The transfer of exogenous Klotho to podocytes of PAN-treated rats could increase miR-30a expression, reduce TRPC6 expression, and also ameliorated podocyte injury and proteinuria. In conclusion, Klotho, acting on miR-30s, which directly regulates its target genes, contributes to podocyte apoptosis induced by PAN. It is a novel mechanism underlying PAN-induced podocyte injury.
Topics: Animals; Calcium Signaling; Cells, Cultured; Dexamethasone; Disease Models, Animal; Down-Regulation; Glucuronidase; Humans; Kidney Diseases; Klotho Proteins; Male; MicroRNAs; Podocytes; Puromycin Aminonucleoside; Rats; Rats, Wistar; TRPC6 Cation Channel
PubMed: 33862465
DOI: 10.1016/j.bbrc.2021.04.003 -
Biochimie Jul 2020EDA2R is a member of the large family of tumor necrosis factor receptor (TNFR). Previous studies suggested that EDA2R expression might be increased in the kidneys of...
EDA2R is a member of the large family of tumor necrosis factor receptor (TNFR). Previous studies suggested that EDA2R expression might be increased in the kidneys of diabetic mice. However, its mRNA and protein expression in kidneys were not analyzed; moreover, its role in the development of diabetic kidney disease was not explored. Here we analyzed the mRNA and protein expressions of EDA2R in diabetic kidneys and examined its role in the podocyte injury in high glucose milieu. By analysis with real-time PCR, Western blotting, we found that both the mRNA and protein levels of EDA2R were increased in the kidneys of diabetic mice. Immunohistochemical studies revealed that EDA2R expression was enhanced in both glomerular and tubular cells of diabetic mice and humans. In vitro studies, high glucose increased EDA2R expression in cultured human podocytes. Overexpression of EDA2R in podocytes promoted podocyte apoptosis and decreased nephrin expression. Moreover, ED2AR increased ROS generation in podocytes, while inhibiting ROS generation attenuates EDA2R-mediated podocyte injury. In addition, EDA2R silencing partially suppressed high glucose-induced ROS generation, apoptosis, and nephrin decrease. Our study demonstrated that high glucose increases EDA2R expression in kidney cells and that EDA2R induces podocyte apoptosis and dedifferentiation in high glucose milieu partially through enhanced ROS generation.
Topics: Animals; Apoptosis; Cells, Cultured; Diabetes Mellitus; Diabetic Nephropathies; Female; Kidney; Membrane Proteins; Mice; Podocytes; RNA, Messenger; Reactive Oxygen Species; Xedar Receptor
PubMed: 32304771
DOI: 10.1016/j.biochi.2020.04.003 -
Kidney International Jul 2009With the recent rise in the prevalence of obesity worldwide, obesity-related albuminuria is now being recognized as a critical risk factor for cardiovascular disease.... (Review)
Review
With the recent rise in the prevalence of obesity worldwide, obesity-related albuminuria is now being recognized as a critical risk factor for cardiovascular disease. However, there is an urgent need for a better understanding of this association. Recent clinical studies suggest that the adipocyte hormone adiponectin may play a key role in the development of obesity-related albuminuria. Moreover, studies with the adiponectin knockout mouse indicate that adiponectin can regulate podocyte function and thus contribute to the initial development of albuminuria. Future studies examining renal adipocyte cell biology are needed to develop preventive and therapeutic strategies for combatting the complications of obesity.
Topics: Adiponectin; Albuminuria; Animals; Humans; Obesity; Podocytes
PubMed: 19404275
DOI: 10.1038/ki.2009.137 -
Zhongguo Dang Dai Er Ke Za Zhi =... Jun 2017All-trans retinoic acid (ATRA) is a vitamin A derivative and plays an important role in the regulation of cell aggregation, differentiation, apoptosis, proliferation,... (Review)
Review
All-trans retinoic acid (ATRA) is a vitamin A derivative and plays an important role in the regulation of cell aggregation, differentiation, apoptosis, proliferation, and inflammatory response. In recent years, some progress has been made in the role of ATRA in renal diseases, especially its protective effect on podocytes. This article reviews the research advances in podocyte injury, characteristics of ATRA, podocyte differentiation and regeneration induced by ATRA, and the protective effect of ATRA against proliferation, deposition of fibers, and apoptosis.
Topics: Apoptosis; Cell Differentiation; Cell Proliferation; Cytoprotection; Humans; Podocytes; Tretinoin
PubMed: 28606243
DOI: 10.7499/j.issn.1008-8830.2017.06.020 -
Journal of the American Society of... Jul 2011Loss of podocytes promotes glomerulosclerosis, but whether this results from a continued primary insult or a secondary mechanism triggered by the initial loss of...
Loss of podocytes promotes glomerulosclerosis, but whether this results from a continued primary insult or a secondary mechanism triggered by the initial loss of podocytes is unknown. We generated chimeric mice in which only a subpopulation of podocytes expressed hCD25, which is the receptor for the immunotoxin LMB2. In addition, genetic labeling of hCD25-negative cells with human placental alkaline phosphatase allowed the study of these two distinct podocyte populations. Administration of LMB2 did not cause podocyte injury in hCD25-negative control mice. In contrast, LMB2 severely damaged or sloughed off the subpopulation of hCD25-positive podocytes within the chimeric glomeruli. Moreover, hCD25-negative podocytes, which were immune to the initial toxin injury, developed injury as early as 4 d after LMB2 injection, evidenced by foot process effacement, upregulation of desmin, and downregulation of nephrin, podocin, and podocalyxin. Furthermore, the magnitude of secondary injury correlated with the magnitude of primary injury, supporting the concept of an amplified cascade of podocyte injury. In conclusion, podocyte damage can propagate injury by triggering secondary damage of "remnant" intact podocytes, even when the primary insult is short-lived. This transmission of podocyte injury may form a vicious cycle leading to accelerated podocyte deterioration and glomerulosclerosis.
Topics: Animals; Chimerism; Female; Interleukin-2 Receptor alpha Subunit; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nephrosclerosis; Podocytes; Transgenes
PubMed: 21719786
DOI: 10.1681/ASN.2010090963