Research Progress on Mechanism of Podocyte Depletion in Diabetic Nephropathy.
Ontology highlight
ABSTRACT:
SUBMITTER: Dai H
PROVIDER: S-EPMC5534294 | biostudies-other | 2017
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Diabetic nephropathy is a multifactorial disease. Gene susceptibility, as well as environmental exposure, plays an important role in disease progression. Malaysia is reported to be among the world's second-fastest-growing rates of kidney failure. Diabetic nephropathy has become the main cause of end-stage renal disease in Malaysia. This article is aimed at reviewing genetic studies conducted among diabetic nephropathy patients in the Malaysian population. This review was conducted by searching PubMed, MEDLINE, and Google Scholar databases to identify all relevant papers published in English from March 2022 to April 2022, using the following keywords: diabetes, type 2 diabetes, diabetic nephropathy, diabetic kidney disease, and Malaysia. The case-control study among diabetic patients with and without diabetic nephropathy showed a significant association with diabetic nephropathy in CNDP1, NOS3, and MnSOD genes. In the ethnic subgroup analysis, significant differences for diabetic nephropathy in terms of diabetes duration (≥10 years) were observed for CCL2 rs3917887, CCR5 rs1799987, ELMO1 rs74130, and IL8 rs4073. The IL8 rs4073 was associated only with the Indians, while the CCR5 rs1799987 was associated with the Chinese. In Malays, SLC12A3 Arg913Gln polymorphism and ICAM1 K469E (A/G) polymorphism were found to be associated with diabetic nephropathy. Studies on gene-environment interactions have suggested significant genetic and environmental factors such as smoking, waist circumference, and sex for eNOS rs2070744, PPARGC1A rs8192678, KCNQ1 rs2237895, and KCNQ1 rs2283228 with kidney disease. The genetic variants' contributions differed across ethnic groups. Therefore, a study to validate the genetic variants that are found to be associated with different ethnicities in Malaysia may be important in future studies.
| S-EPMC10181909 | biostudies-literature
Project description:Apoptosis, one of the major causes of podocyte loss, has been reported to have a vital role in diabetic nephropathy (DN) pathogenesis, and understanding the mechanisms underlying the regulation of podocyte apoptosis is crucial. Metadherin (MTDH) is an important oncogene, which is overexpressed in most cancers and responsible for apoptosis, metastasis, and poor patient survival. Here we show that the expression levels of Mtdh and phosphorylated p38 mitogen-activated protein kinase (MAPK) are significantly increased, whereas those of the microRNA-30 family members (miR-30s) are considerably reduced in the glomeruli of DN rat model and in high glucose (HG)-induced conditionally immortalized mouse podocytes (MPC5). These levels are positively correlated with podocyte apoptosis rate. The inhibition of Mtdh expression, using small interfering RNA, but not Mtdh overexpression, was shown to inhibit HG-induced MPC5 apoptosis and p38 MAPK pathway, and Bax and cleaved caspase 3 expression. This was shown to be similar to the effects of p38 MAPK inhibitor (SB203580). Furthermore, luciferase assay results demonstrated that Mtdh represents the target of miR-30s. Transient transfection experiments, using miR-30 microRNA (miRNA) inhibitors, led to the increase in Mtdh expression and induced the apoptosis of MPC5, whereas the treatment with miR-30 miRNA mimics led to the reduction in Mtdh expression and apoptosis of HG-induced MPC5 cells in comparison with their respective controls. Our results demonstrate that Mtdh is a potent modulator of podocyte apoptosis, and that it represents the target of miR-30 miRNAs, facilitating podocyte apoptosis through the activation of HG-induced p38 MAPK-dependent pathway.
| S-EPMC5260885 | biostudies-literature
Project description: Not available
| S-EPMC8184495 | biostudies-literature
Project description:BackgroundGlomerular podocyte number declines and urinary excretion of podocytes increases as kidney disease progresses in persons with type 2 diabetes mellitus (T2DM).MethodsUsing high-power electron microscopy, we quantified podocyte detachment in T2DM.ResultsWe evaluated 106 glomeruli (range 1-6 per subject) from 40 Pima Indian subjects with T2DM enrolled in a clinical trial. On high-power electron micrographs, 35% of the subjects had no evidence of podocyte detachment. Among the remaining subjects, the median percentage of basement membrane with podocyte detachment was 0.62% (interquartile range = 0.32-1.52%).ConclusionPodocyte detachment from the glomerular basement membrane has been described and measured in type 1 diabetes mellitus using a different method. We now document podocyte detachment microscopically and quantify it morphometrically in humans with T2DM. The findings offer quantitative histologic support to a potential mechanism for the functional impairment, and possibly the sclerosis of glomeruli, in diabetic glomerular injury.
| S-EPMC3121550 | biostudies-literature
Project description:Podocyte injury and resulting albuminuria are hallmarks of diabetic nephropathy, but targeted therapies to halt or prevent these complications are currently not available. Here, we show that the immune-related molecule B7-1/CD80 is a critical mediator of podocyte injury in type 2 diabetic nephropathy. We report the induction of podocyte B7-1 in kidney biopsy specimens from patients with type 2 diabetes. Genetic and epidemiologic studies revealed the association of two single nucleotide polymorphisms at the B7-1 gene with diabetic nephropathy. Furthermore, increased levels of the soluble isoform of the B7-1 ligand CD28 correlated with the progression to ESRD in individuals with type 2 diabetes. In vitro, high glucose conditions prompted the phosphatidylinositol 3 kinase-dependent upregulation of B7-1 in podocytes, and the ectopic expression of B7-1 in podocytes increased apoptosis and induced disruption of the cytoskeleton that were reversed by the B7-1 inhibitor CTLA4-Ig. Podocyte expression of B7-1 was also induced in vivo in two murine models of diabetic nephropathy, and treatment with CTLA4-Ig prevented increased urinary albumin excretion and improved kidney pathology in these animals. Taken together, these results identify B7-1 inhibition as a potential therapeutic strategy for the prevention or treatment of diabetic nephropathy.
| S-EPMC4073425 | biostudies-literature
Project description:Background Diabetic nephropathy (DN) is a leading cause of ESRD in the United States, but the molecular mechanisms mediating the early stages of DN are unclear.Methods To assess global changes that occur in early diabetic kidneys and to identify proteins potentially involved in pathogenic pathways in DN progression, we performed proteomic analysis of diabetic and nondiabetic rat glomeruli. Protein S (PS) among the highly upregulated proteins in the diabetic glomeruli. PS exerts multiple biologic effects through the Tyro3, Axl, and Mer (TAM) receptors. Because increased activation of Axl by the PS homolog Gas6 has been implicated in DN progression, we further examined the role of PS in DN.Results In human kidneys, glomerular PS expression was elevated in early DN but suppressed in advanced DN. However, plasma PS concentrations did not differ between patients with DN and healthy controls. A prominent increase of PS expression also colocalized with the expression of podocyte markers in early diabetic kidneys. In cultured podocytes, high-glucose treatment elevated PS expression, and PS knockdown further enhanced the high-glucose-induced apoptosis. Conversely, PS overexpression in cultured podocytes dampened the high-glucose- and TNF-α-induced expression of proinflammatory mediators. Tyro3 receptor was upregulated in response to high glucose and mediated the anti-inflammatory response of PS. Podocyte-specific PS loss resulted in accelerated DN in streptozotocin-induced diabetic mice, whereas the transient induction of PS expression in glomerular cells in vivo attenuated albuminuria and podocyte loss in diabetic OVE26 mice.Conclusions Our results support a protective role of PS against glomerular injury in DN progression.
| S-EPMC5967770 | biostudies-literature
Project description:In diabetic nephropathy (DN), podocyte cytoskeletal rearrangement occurs followed by podocyte effacement and the development of proteinuria. PTEN (phosphatase and tensin homologue) is a ubiquitously expressed phosphatase that plays a critical role in cell proliferation, cytoskeletal rearrangement, and motility. In mouse models of diabetes mellitus, PTEN expression is reportedly decreased in mesangial cells, contributing to expansion of the mesangial matrix, but how PTEN in the podocyte influences the development of DN is unknown. We observed that PTEN expression is down-regulated in the podocytes of diabetic db/db mice and patients with DN. In cultured podocytes, PTEN inhibition caused actin cytoskeletal rearrangement and this response was associated with unbalanced activation of the small GTPases Rac1/Cdc42 and RhoA. In mice treated with PTEN inhibitor, actin cytoskeletal rearrangement occurred in podocytes and was accompanied by increased albumin excretion. We also created mice with an inducible deletion of PTEN selectively in podocytes. These mice exhibited increased albumin excretion and moderate foot process effacement. When the mice were challenged with a high fat diet, podocyte-specific knockout of PTEN resulted in substantially increased proteinuria and glomeruloclerosis compared to control mice fed a high fat diet or mice with PTEN deletion fed a normal diet. These results indicate that PTEN is involved in the regulation of cytoskeletal rearrangement in podocytes and that loss of PTEN predisposes to the development of proteinuria and DN.
| S-EPMC4398628 | biostudies-literature
Project description:Diabetic kidney disease (DKD) is one of the serious microvascular complications of diabetes mellitus (DM), and it is also the leading cause for the end-stage kidney disease (ESKD), but the clinical treatment for it is limited at present. The pathogenesis of DKD is complex. Many studies have shown that podocyte injury is the core event of DKD, and oxidative stress is closely related to podocyte injury in DKD. Oxidative stress mediates podocyte apoptosis and slit diaphragm damage in DKD through various pathways. The antioxidant drugs can slow down the progression of DKD through reducing podocyte injury and are expected to enter clinical trials. The research status of antioxidant drugs is very important, which will provide new strategies for the clinical treatment of DKD.
| S-EPMC10930572 | biostudies-literature
Project description:Background Renal glomeruli are the primary target of injury in diabetic nephropathy (DN), and the glomerular podocyte has a key role in disease progression.Methods To identify potential novel therapeutic targets for DN, we performed high-throughput molecular profiling of G protein-coupled receptors (GPCRs) using human glomeruli.Results We identified an orphan GPCR, Gprc5a, as a highly podocyte-specific gene, the expression of which was significantly downregulated in glomeruli of patients with DN compared with those without DN. Inactivation of Gprc5a in mice resulted in thickening of the glomerular basement membrane and activation of mesangial cells, which are two hallmark features of DN in humans. Compared with wild-type mice, Gprc5a-deficient animals demonstrated increased albuminuria and more severe histologic changes after induction of diabetes with streptozotocin. Mechanistically, Gprc5a modulated TGF-? signaling and activation of the EGF receptor in cultured podocytes.Conclusions Gprc5a has an important role in the pathogenesis of DN, and further study of the podocyte-specific signaling activity of this protein is warranted.
| S-EPMC6054345 | biostudies-literature
Project description:Activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) has been implicated in diverse kidney diseases, yet its in vivo significance in diabetic nephropathy (DN) is largely unknown. In the present study, we demonstrated a podocyte-specific Rac1-deficient mouse strain and showed that specific inhibition of Rac1 was able to attenuate diabetic podocyte injury and proteinuria by the blockade of Rac1/PAK1/p38/β-catenin signaling cascade, which reinstated the integrity of podocyte slit diaphragms (SD), rectified the effacement of foot processes (FPs), and prevented the dedifferentiation of podocytes. In vitro, we showed Rac1/PAK1 physically bound to β-catenin and had a direct phosphorylation modification on its C-terminal Ser675, leading to less ubiquitylated β-catenin, namely more stabilized β-catenin, and its nuclear migration under high-glucose conditions; further, p38 activation might be responsible for β-catenin nuclear accumulation via potentiating myocyte-specific enhancer factor 2C (MEF2c) phosphorylation. These findings provided evidence for a potential renoprotective and therapeutic strategy of cell-specific Rac1 deficiency for DN and other proteinuric diseases.
| S-EPMC5832796 | biostudies-literature