Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction

Nat Med. 2017 Jun;23(6):753-762. doi: 10.1038/nm.4328. Epub 2017 Apr 24.


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.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Blotting, Western
  • Cell Line
  • Diabetes Mellitus / metabolism*
  • Diabetes Mellitus, Experimental
  • Diabetic Nephropathies / metabolism*
  • Female
  • Fluorescent Antibody Technique
  • Gene Knockdown Techniques
  • Glucose / metabolism*
  • Glycolysis
  • Humans
  • Kidney / metabolism
  • Kidney Glomerulus / metabolism
  • Male
  • Membrane Potential, Mitochondrial*
  • Metabolomics
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Mitochondria / metabolism*
  • Nitric Oxide Synthase Type III / genetics
  • Organelle Biogenesis
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Podocytes / metabolism*
  • Proteomics
  • Pyruvate Kinase / genetics*
  • Pyruvate Kinase / metabolism
  • Reactive Oxygen Species / metabolism
  • Real-Time Polymerase Chain Reaction


  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Reactive Oxygen Species
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Pyruvate Kinase
  • Glucose