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

• Published in: Nature medicine Vol. 23; no. 6; pp. 753 - 762
• Main Authors: Qi, Weier, Keenan, Hillary A, Li, Qian, Ishikado, Atsushi, Kannt, Aimo, Sadowski, Thorsten, Yorek, Mark A, Wu, I-Hsien, Lockhart, Samuel, Coppey, Lawrence J, Pfenninger, Anja, Liew, Chong Wee, Qiang, Guifen, Burkart, Alison M, Hastings, Stephanie, Pober, David, Cahill, Christopher, Niewczas, Monika A, Israelsen, William J, Tinsley, Liane, Stillman, Isaac E, Amenta, Peter S, Feener, Edward P, Vander Heiden, Matthew G, Stanton, Robert C, King, George L
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2017; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/51; 14/19; 14/28; 631/443/319/1642; 692/699/1585/2759; 82/51; 96/2; 96/31; Aged; Aged, 80 and over; Animals; Biomedicine; Blotting, Western; Cancer Research; Cell Line; Chronic kidney failure; Development and progression; Diabetes; Diabetes Mellitus - metabolism; Diabetes Mellitus, Experimental; Diabetic nephropathies; Diabetic Nephropathies - metabolism; Enzymes; Female; Fluorescent Antibody Technique; Gene Knockdown Techniques; Glucose; Glucose - metabolism; Glycolysis; Health aspects; Humans; Hyperglycemia; Infectious Diseases; Kidney - metabolism; Kidney Glomerulus - metabolism; Kinases; Male; Medical research; Membrane Potential, Mitochondrial; Metabolic Diseases; Metabolism; Metabolites; Metabolomics; Mice; Mice, Knockout; Middle Aged; Mitochondria - metabolism; Molecular Medicine; Neurosciences; Nitric Oxide Synthase Type III - genetics; Organelle Biogenesis; Pathogenesis; Pathology; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Podocytes - metabolism; Proteomics; Pyruvate kinase; Pyruvate Kinase - genetics; Pyruvate Kinase - metabolism; Reactive Oxygen Species - metabolism; Real-Time Polymerase Chain Reaction; Sorbitol; Type 2 diabetes; Beijing China; United States > US; Massachusetts; China
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4328

Studying patients with long-term diabetes who lack diabetic nephropathy reveals that targeting pyruvate kinase M2 protects against renal disease. 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.