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

Weier Qi; Hillary A Keenan; Qian Li; Atsushi Ishikado; Aimo Kannt; Thorsten Sadowski; Mark A Yorek; I-Hsien Wu; Samuel Lockhart; Lawrence J Coppey; Anja Pfenninger; Chong Wee Liew; Guifen Qiang; Alison M Burkart; Stephanie Hastings; David Pober; Christopher Cahill; Monika A Niewczas; William J Israelsen; Liane Tinsley; Isaac E Stillman; Peter S Amenta; Edward P Feener; Matthew G Vander Heiden; Robert C Stanton; George L King

doi:10.1038/nm.4328

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

Journal article

Peer reviewed

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

Weier Qi, Hillary A Keenan, Qian Li, Atsushi Ishikado, Aimo Kannt, Thorsten Sadowski, Mark A Yorek, I-Hsien Wu, Samuel Lockhart, Lawrence J Coppey, …

Nature medicine, Vol.23(6), pp.753-762

06/2017

DOI: 10.1038/nm.4328

PMCID: PMC5575773

PMID: 28436957

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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 (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.

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

Details

Title: Subtitle: Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction
Creators: Weier Qi - Joslin Diabetes Center
Hillary A Keenan - Joslin Diabetes Center
Qian Li - Joslin Diabetes Center
Atsushi Ishikado - Joslin Diabetes Center
Aimo Kannt - Aventis Pharma
Thorsten Sadowski - Aventis Pharma
Mark A Yorek - Veterans Health Administration
I-Hsien Wu - Joslin Diabetes Center
Samuel Lockhart - Queen's University Belfast
Lawrence J Coppey - Veterans Health Administration
Anja Pfenninger - Aventis Pharma
Chong Wee Liew - University of Illinois Chicago
Guifen Qiang - University of Illinois Chicago
Alison M Burkart - Joslin Diabetes Center
Stephanie Hastings - Joslin Diabetes Center
David Pober - Joslin Diabetes Center
Christopher Cahill - Joslin Diabetes Center
Monika A Niewczas - Joslin Diabetes Center
William J Israelsen - The University of Texas Southwestern Medical Center
Liane Tinsley - Joslin Diabetes Center
Isaac E Stillman - Beth Israel Deaconess Medical Center
Peter S Amenta - Joslin Diabetes Center
Edward P Feener - Joslin Diabetes Center
Matthew G Vander Heiden - Massachusetts Institute of Technology
Robert C Stanton - Joslin Diabetes Center
George L King - Joslin Diabetes Center
Resource Type: Journal article
Publication Details: Nature medicine, Vol.23(6), pp.753-762
DOI: 10.1038/nm.4328
PMID: 28436957
PMCID: PMC5575773
NLM abbreviation: Nat Med
ISSN: 1078-8956
eISSN: 1546-170X
Grant note: R01 DK107399 / NIDDK NIH HHS K99 DK090210 / NIDDK NIH HHS R24 DK090961 / NIDDK NIH HHS P30 DK036836 / NIDDK NIH HHS R01 DK109015 / NIDDK NIH HHS DP3 DK112192 / NIDDK NIH HHS DP3 DK094333 / NIDDK NIH HHS R00 DK090210 / NIDDK NIH HHS
Language: English
Date published: 06/2017
Academic Unit: Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984359885602771

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