Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are limited. To identify novel therapeutic strategies, we studied protective factors for DN using proteomics on glomeruli from individuals with extreme duration of diabetes (ł50 years) without DN and those with histologic signs of DN. Enzymes in the glycolytic, sorbitol, methylglyoxal and mitochondrial pathways were elevated in individuals without DN. In particular, pyruvate kinase M2 (PKM2) expression and activity were upregulated. Mechanistically, we showed that hyperglycemia and diabetes decreased PKM2 tetramer formation and activity by sulfenylation in mouse glomeruli and cultured podocytes. Pkm-knockdown immortalized mouse podocytes had higher levels of toxic glucose metabolites, mitochondrial dysfunction and apoptosis. Podocyte-specific Pkm2-knockout (KO) mice with diabetes developed worse albuminuria and glomerular pathology. Conversely, we found that pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, reversed hyperglycemia-induced elevation in toxic glucose metabolites and mitochondrial dysfunction, partially by increasing glycolytic flux and PGC-1α mRNA in cultured podocytes. In intervention studies using DBA2/J and Nos3 (eNos) KO mouse models of diabetes, TEPP-46 treatment reversed metabolic abnormalities, mitochondrial dysfunction and kidney pathology. Thus, PKM2 activation may protect against DN by increasing glucose metabolic flux, inhibiting the production of toxic glucose metabolites and inducing mitochondrial biogenesis to restore mitochondrial function.
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We are grateful to all the fellows who participated in Medalist Kidneys collection, D. Anastasiou, J. Lee, C. Thomas and M. Lauterbach for their technical advice. We also thank the technical support from E. Yu, daily-oral-gavaging team members, Z. Zsengeller and E. Pernicone. We are grateful to M. Maurer, who gave us technical advice on human kidney pathology assessment. We thank C. Clish for plasma metabolomics analysis. We are grateful to J. Hourihan for technical advice and review of the manuscript. W. Qi was a recipient of awards from the Juvenile Diabetes Research Foundation and Mary Iacocca Research Foundation. Mouse podocytes and human podocytes cell lines were kind gifts from P.M. and J.K. This project was funded by NIH 1DP3DK112192-01 (G.L.K.); DK094333-01 (G.L.K. and H.A.K.), 1R24DK090961-01 (G.L.K.); DRC grant-P30DK036836-30 (G.L.K.); JDRF 8-2005-358 (G.L.K.); JDRF 18-2008-363 (G.L.K.); JDRF17-2011-47 (G.L.K.); and JDRF17-2013-310 (H.A.K.). Additional research support was provided by the Thomas Beatson, Jr Foundation, the Brehm Foundation and a research grant from Sanofi-Aventis (G.L.K.). Other co-authors were supported by the following funding: DK107339-02 (M.A.Y.); Harold Whitworth Pierce Charitable Trust Postdoctoral Fellowship (A.M.B.); R01 DK109015 and R00 DK090210 (C.W.L.) and JDRF CDA-2015-89-A-B (M.A.N.).
A.K., T.S. and A.P. are employees of Sanofi-Aventis.
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Qi, W., Keenan, H., Li, Q. et al. Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction. Nat Med 23, 753–762 (2017). https://doi.org/10.1038/nm.4328
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