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
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
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Research Article Endocrinology Metabolism

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

Abstract

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.

Authors

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

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Figure 5

PPKM2Tg mice showed improvement of glomerular mitochondrial function and glycolysis 7 months after STZ.

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PPKM2Tg mice showed improvement of glomerular mitochondrial function and...
(A and C) OCR (A) and ECAR (C) in the glomeruli of WT and PPKM2Tg mice 7 months after STZ were measured by Seahorse. (B and D) The quantitated data from A and C. For OCR A and B, WT mice (n = 21); PPKM2Tg mice (n = 13); WT 7MSTZ mice (n = 11); Tg 7MSTZ mice (n = 13). *P < 0.05; **P < 0.01. For ECAR C and D, WT mice (n = 6); PPKM2Tg mice (n = 8); WT 7MSTZ mice (n = 4); Tg 7MSTZ mice (n = 6). *P < 0.05; **P < 0.01. Mouse recombinant VEGF (2 ng/mL), VEGF neutralizing antibody (anti-VEGF) (1 μg/mL), and premix of mVEGF with anti-VEGF were incubated for 2 hours in WT glomeruli. (E–H) OCR (E) and ECAR (G) were measured and quantitated data were presented (F and H). For OCR (E and F), control group (n = 14); mVEGF group (n = 7); anti-VEGF group (n = 6); mVEGF + anti-VEGF group (n = 5). *P < 0.05. For ECAR (G and H), control group (n = 7); mVEGF group (n = 8); anti-VEGF group (n = 3); mVEGF + anti-VEGF group (n = 5). **P < 0.01. Data are mean ± SEM, 2-way ANOVA followed by correction for multiple comparisons with Tukey’s post hoc test.