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Pyruvate kinase M2 activation may protect against the progression of diabetic
glomerular pathology and mitochondrial dysfunction.
Authors Qi W, Keenan HA, Li Q, Ishikado A, Kannt A, Sadowski T, Yorek MA, Wu IH,
Lockhart S, Coppey LJ, Pfenninger A, Liew CW, Qiang G, Burkart AM, Hastings S,
Pober D, Cahill C, Niewczas MA, Israelsen WJ, Tinsley L, Stillman IE, Amenta PS,
Feener EP, Vander Heiden MG, Stanton RC, King GL
Submitted By Hillary Keenan on 5/1/2017
Status Published
Journal Nature medicine
Year 2017
Date Published 4/1/2017
Volume : Pages Not Specified : Not Specified
PubMed Reference 28436957
Abstract 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 (l50
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-1a 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.