Abstract
Diabetic nephropathy (DN) is the result of systemic and local changes in metabolism and hemodynamics. We have found that the elevation of glycolytic enzymes, such as pyruvate kinase M2 (PKM2) in the renal glomeruli is correlated with preservation of renal function in human type 1 and type 2 diabetes. A small-molecule PKM2 activator, TEPP46, prevented or reversed glomerular pathology in diabetic mice of chronic duration. Mice with PKM2 overexpression specifically in podocytes (PPKM2Tg) were generated, which after 7 months of diabetes induced by streptozotocin, exhibited significantly lower albumin-creatinine ratio (ACR), kidney weight-body weight ratio, and glomeruli pathology such as reduced glomeruli size, mesangial expansion, and basement membrane thickness compared to diabetic WT mice. Furthermore, the glomeruli of diabetic PPKM2Tg mice exhibited lower expressions of fibrotic (FN, TGFβ1 and Col4a) and oxidative stress (p47phox, NOX2 and NOX4) genes compared to WT diabetic mice. Interestingly, the decreased expression of endothelial-trophic genes and mitochondrial-related genes were improved in the whole glomeruli of diabetic PPKM2Tg mice. Oxygen consumption rate (OCR) of glomeruli as measured by Seahorse showed significant improvement in diabetic PPKM2Tg mice versus WT mice (p < 0.05). In vitro studies showed that the activation of PKM2 in mouse podocyte cell line by TEPP-46 decreased high glucose-induced ROS production, improved mitochondrial membrane potential (MMP) by increased the level of mitochondrial OCR and enhanced glycolytic rate. Furthermore, PKM-knockdown stable podocyte cell line, mimicking diabetic conditions, showed dramatical decline of OCR and glycolytic rate. These results showed that PKM2 specific overexpression in podocytes can significantly reduce diabetes-induced mitochondrial abnormalities and oxidative stress in the whole glomeruli, and delay the progression of diabetic nephropathy. Disclosure J. Fu: None. T. Shinjo: None. R. St-Louis: None. Q. Li: None. K. Park: None. H. Yokomizo: None. Y. Zaitsu: Employee; Self; Sunstar Group. M. Yu: None. I. Wu: None. H. Shah: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.
Published Version
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