Elevated expression of pyruvate kinase isoform M2 (PKM2) in the renal glomeruli of people with diabetes is associated with protection from nephropathy even with hyperglycemia. Furthermore, systemic use of PKM2 activators (TEPP46) can prevent or reverse glomerular pathology in diabetic mice. To determine specifically the role of PKM2 in the development or progression of diabetic glomerulopathy, we generated transgenic mice overexpressing PKM2 specific targeted to the podocytes (PPKM2Tg mice) driven by the podocin promoter. Analysis of the glomeruli from these mice showed 1.5-fold increases in mRNA and protein levels without changes in PKM1, compared to wild type (WT) littermates (p<0.05). Pyruvate kinase (PK) activity in the glomeruli of the PPKM2Tg mice was increased by 40% compared to those in WT mice (p<0.05). Diabetes was induced in eight-week-old WT and PPKM2Tg mice by streptozotocin (STZ) and maintained with sustained glucose levels >400mg/dL for 7 months. Diabetic PPKM2Tg mice showed significantly lower urinary albumin-creatinine ratio (ACR) and kidney weight-body weight ratios (p<0.05) compared to diabetic WT mice even with similar hyperglycemia. PK activity was lowered in the glomeruli of diabetic WT mice by 30%, whereas levels in diabetic PPKM2Tg mice were comparable to nondiabetic WT mice. For renal pathology, diabetic PPKM2Tg mice exhibited smaller glomeruli compared to diabetic WT mice. Similarly, expressions of inflammatory genes including TNFα and MCP-1, and fibrotic genes including fibronectin and TGF-β1 were downregulated in the glomeruli of diabetic PPKM2Tg mice compared to diabetic WT mice. In contrast, mitochondrial genes such as PGC-1α, Opa1, and cytochrome b in the glomeruli of diabetic PPKM2Tg mice were significantly upregulated as compared to diabetic WT mice. These findings strongly suggest that upregulation or activation of PKM2 and glycolysis may improve mitochondrial function in podocytes and prevent the progression of diabetic nephropathy.
T. Shinjo: None. R. St-Louis: None. J. Fu: None. K. Park: None. Q. Li: None. H. Yokomizo: None. M. Yu: None. H. Wang: None. A. Kannt: Employee; Self; Sanofi. T. Sadowski: Employee; Self; Sanofi-Aventis Deutschland GmbH. G.L. King: Research Support; Self; Sanofi.
National Institutes of Health; Sanofi