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 1

PPKM2Tg mice were resistant to diabetes-induced kidney injury.

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PPKM2Tg mice were resistant to diabetes-induced kidney injury. (A) Schem...
(A) Schema of PPKM2Tg mice generation. The complete mouse cDNA sequence of PKM2 (1.6 kb) was inserted to mouse Nphs2 promoter (1.1 kb) constructor. (B–D) Western blotting of PKM2, PKM1, podocyte marker (nephrin, podocin), and proximal tubule marker AQP1 in glomeruli, tubule, and cortex of PPKM2Tg and WT mice (n = 3 per group, *P < 0.05 versus WT). (B) Representative image. (C and D) Quantification of data. (E) PK activity in glomeruli, tubule, and cortex of PPKM2Tg and WT mice. (WT [n = 4], PPKM2Tg [n = 3]; *P < 0.05 versus WT). (F) Schema of prevention study designed using STZ-induced diabetic WT (WT 7MSTZ) or PPKM2Tg mice (Tg 7MSTZ). Mice were given 5 consecutive days of i.p. injections of 50 mg streptozotocin (STZ)/kg body weight (50 mg/kg) or vehicle at age of 8 weeks, and they were harvested after 7 months since diabetes onset. (G) Fasting blood glucose 7 months after STZ. (H) Kidney weight/body weight ratio 7 months after STZ. (I) Albumin creatinine ratio 7 months after STZ. Nondiabetic WT mice (n = 3); PPKM2Tg mice (n = 3); WT 7MSTZ mice (n = 6); Tg 7MSTZ mice (n = 6). *P < 0.05; **P < 0.01. Data are mean ± SEM, 2-way ANOVA followed by correction for multiple comparison.