Biology subjects

Koya, D.

Publications and source records attributed to Koya, D..

3 recordsLinked to original sources

bioRxiv2025

Metabolic reprogramming by endothelial ANGPTL4 depletion protects against diabetic kidney disease

The role of cell-specific ANGPTL4 is not well known in the context of ECs, specifically in pathological angiogenesis and its relation to diabetic kidney disease. Here, we demonstrate that endothelial ANGPTL4 is required to induce a metabolic phenotype that favors mesenchymal activation in ECs and tubules in diabetic conditions. Diabetes accelerates mesenchymal activation and fibrogenesis in control mice however, the same effects were not observed in endothelial-cell specific knock out mice. This mesenchymal activation in diabetes is directly linked with pathological neovascularization, endothelial leakage, lipid and glycolysis metabolite load, de novo lipogenesis (DNL) and related mitochondrial damage, activation of the immune system, c-GAS-STING activation and transcription of pro-inflammatory cytokines. However, endothelial ANGPTL4-depleted mice had stable vessels, improved levels of lipid and glucose metabolism, suppressed levels of DNL, restored mitochondrial function, and mitigated levels of c-GAS-STING-mediated inflammation. Moreover, Inhibition of DNL, and STING via small molecule inhibitors suppressed pathological neovascularization and endothelial leakage, normalized fatty acid oxidation and reduced pathological glycolysis and de novo lipogenesis (DNL). These data demonstrate the crucial roles of endothelial ANGPTL4 in regulating pathogenic angiogenesis in the renal vasculature during diabetes.

molecular biology↗

bioRxiv2023

Renal Angptl4 is a key fibrogenic molecule in progressive diabetic kidney disease

Angiopoietin-like 4 (ANGPTL4) is the key protein involved in lipoprotein metabolism and has been shown to have diverse effects on tissue protection. In clinical settings, there is a reported association between higher levels of plasma Angptl4 and features of diabetic kidney disease, however, the association between kidney Angptl4 with features of diabetic kidney disease has not been well investigated. We show that both podocyte-and tubule-specific ANGPTL4 are crucial fibrogenic molecules in diabetes. Results from mRNA-array analysis in control (non-fibrotic) and diabetic (fibrotic) kidneys suggest time-dependent emergence of Angplt4 expression. Diabetes accelerates the fibrogenic phenotype in control mice but not in ANGPTL4 mutant mice. The protective effect observed in ANGPTL4 mutant mice is correlated with a reduction in the levels of pro-inflammatory cytokines, epithelial-to-mesenchymal transition, endothelial-to-mesenchymal transition and augmented fatty acid oxidation. Mechanistically, we demonstrate that podocyte-or tubule-secreted Angptl4 interacts with Integrin-{beta}1 and influences the association between dipeptidyl-4 with Integrin-{beta}1 and promotes heterodimerization of transforming growth factor-{beta} receptor 1 (TGF{beta}R1) and TGF{beta}R2 in cultured cells. This in turn results in Smad3 phosphorylation and subsequent downregulation of the expression of genes involved in fatty acid oxidation; these cumulative effects led to the activation of fibrogenic phenotypes. We demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits Angptl4 gene expression in the kidneys and protects diabetic kidneys from proteinuria and fibrosis. Importantly, use of this kidney-specific targeted strategy is beneficial and does not cause any harmful effect suggesting it can be used as a novel drug molecule for treatment of diabetic kidney disease. Taken together, these data demonstrate that podocyte-and tubule-derived Angptl4 is fibrogenic in diabetic kidneys.

cell biology↗

bioRxiv2020

Endothelial SIRT3 regulates myofibroblast metabolic shifts in diabetic kidneys

Defects in endothelial cells cause deterioration in kidney function and structure. Here, we found that endothelial SIRT3 regulates metabolic reprogramming and fibrogenesis in the kidneys of diabetic mice. By analyzing, gain-of-function of the SIRT3 gene by overexpression in a fibrotic mouse strain conferred disease resistance against diabetic kidney fibrosis; while its loss-of-function in endothelial cells exacerbated the levels of diabetic kidney fibrosis. Regulation of endothelial cell SIRT3 on fibrogenic processes was due to tight control over the defective central metabolism and linked-activation of endothelial-to-mesenchymal transition (EndMT). SIRT3 deficiency in endothelial cells stimulated the TGF{beta}/Smad3-depandent mesenchymal transformations in renal tubular epithelial cells. These data demonstrate that SIRT3 regulates defective metabolism and EndMT-mediated activation of the fibrogenic pathways in the diabetic kidneys. Together, our findings show that endothelial cell SIRT3 is a fundamental regulator of defective metabolism regulating health and disease processes in the kidney. Context and significanceThe present study describes that endothelial cell SIRT3 protects against renal fibrosis by mitigating the metabolic reprogramming and associated mesenchymal transformations in diabetes. Accordingly, amelioration of endothelial cell SIRT3 and targeting the defective metabolism offer a potential therapeutic approach to treat or prevent the progression of diabetic kidney disease. Further investigation would delineate the mechanisms of SIRT3 up-regulation in diabetic kidney disease and discover small molecules to increase the expression of the SIRT3. In addition, this study describes the biology of SIRT3 in the health and disease processes of kidney endothelial cells.

cell biology↗