24-OR: Podocyte Targeted Pyruvate Kinase M2 (PKM2) Activation Normalized Glomerular VEGF Expression, Mitochondrial Function, Fuel Metabolism, and Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is the result of abnormal systemic and local changes in metabolism and hemodynamics. We have reported that many glycolytic enzymes, such as pyruvate kinase M2 (PKM2) , were elevated in the renal glomeruli of type 1 and type 2 diabetic patients who were protected from DN. TEPP46, a small-molecule which activates PKM2 by inducing oligomerization, reversed glomerular pathology in diabetic mice. Here, mice with PKM2-specific overexpression in podocytes (PPKM2Tg) were generated to uncover its renal protective function as potential therapeutic target, which prevented elevated albumin-creatinine ratio (ACR) , mesangial expansion, basement membrane thickness and podocyte foot process effacement after 7-months of STZ-induced diabetes. Further, diabetes-induced impairment of glycolytic rate and mitochondrial function were normalized in diabetic PPKM2Tg glomeruli, in concordance with elevated Ppargc1a and Vegf expressions. Restored VEGF expression improved glomerular maximal mitochondrial function in diabetic PPKM2Tg and WT mice. Elevated VEGF levels were observed in the glomeruli of DN-protected patients with chronic type 1 diabetes, and clinically correlated with estimated GFR, but not glycemic control. Mechanistically, the preservations of mitochondrial function and VEGF expression were dependent on tetrameric structure and enzymatic activities of PKM2 in podocyte. Thus, these findings show that PKM2 activation in the podocyte can regulate mitochondrial metabolism of the entire glomeruli and prevent mitochondrial dysfunction induced by chronic diabetes and even reverse metabolic memory. PKM2 structures and enzymatic activities are necessary to mediate glomerular metabolism against toxicity of hyperglycemia via paracrine factors such as VEGF. Thus, PKM2 activation in podocyte is a potential therapeutic target to protect against DN. Disclosure J.Fu: None. T.Shinjo: None. Q.Li: None. K.Park: None. M.Yu: None. H.Yokomizo: None. Q.Huang: None. I.Wu: None. G.L.King: Advisory Panel; Medtronic, Research Support; Janssen Pharmaceuticals, Inc.