Regeneration of glomerular metabolism and function by podocyte pyruvate kinase M2 in diabetic nephropathy.

Jialin Fu, Takanori Shinjo, Qian Li, Ronald St-Louis, Kyoungmin Park, Marc G Yu, Hisashi Yokomizo, Fabricio Simao, Qian Huang, I-Hsien Wu, George L King

JCI insight 2022 Mar 08

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Diabetic nephropathy (DN) arises from systemic and local changes in glucose metabolism and hemodynamics. We have reported that many glycolytic and mitochondrial enzymes, such as pyruvate kinase M2 (PKM2), were elevated in renal glomeruli of DN-protected patients with type 1 and type 2 diabetes. Here, mice with PKM2 overexpression specifically in podocytes (PPKM2Tg) were generated to uncover the renal protective function of PPKM2Tg as a potential therapeutic target that prevented elevated albumin/creatinine ratio (ACR), mesangial expansion, basement membrane thickness, and podocyte foot process effacement after 7 months of streptozotocin-induced (STZ-induced) diabetes. Furthermore, diabetes-induced impairments 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 glomerular filtration (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 podocytes. These findings demonstrate that PKM2 structure and enzymatic activation in podocytes can preserve the entire glomerular mitochondrial function against toxicity of hyperglycemia via paracrine factors such as VEGF and prevent DN progression.

Citation

Jialin Fu, Takanori Shinjo, Qian Li, Ronald St-Louis, Kyoungmin Park, Marc G Yu, Hisashi Yokomizo, Fabricio Simao, Qian Huang, I-Hsien Wu, George L King. Regeneration of glomerular metabolism and function by podocyte pyruvate kinase M2 in diabetic nephropathy. JCI insight. 2022 Mar 08;7(5)