Dataset Information

LC-MS/MS proteomics on glomeruli from individuals with extreme duration of type 1 diabetes

ABSTRACT: Diabetic nephropathy (DN) is a major cause of end-stage renal disease and has limited therapeutic options to prevent its progression. To identify novel therapeutic strategies, protective factors for DN were studied using proteomics on glomeruli from 50-year medalists (individuals with extreme duration, ≥50 years, of diabetes in Joslin Medalist Study) without DN and those with histologic signs of DN. Many enzymes in the glycolytic, sorbitol, methylglyoxal and mitochondrial pathways were elevated in individuals without DN. We also identified that pyruvate kinase M2 (PKM2) expression and activity were upregulated. We then looked into the mechanisms and further validated the findings in vivo (Podocyte-specific Pkm2 KO mice model) and in vitro (cultured podocytes).

INSTRUMENT(S): LTQ

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney

DISEASE(S): Type 1 Diabetes Mellitus

SUBMITTER: I-Hsien Wu

LAB HEAD: George King

PROVIDER: PXD006339 | Pride | 2017-05-02

REPOSITORIES: Pride

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

Qi Weier W Keenan Hillary A HA Li Qian Q Ishikado Atsushi A Kannt Aimo A Sadowski Thorsten T Yorek Mark A MA Wu I-Hsien IH Lockhart Samuel S Coppey Lawrence J LJ Pfenninger Anja A Liew Chong Wee CW Qiang Guifen G Burkart Alison M AM Hastings Stephanie S Pober David D Cahill Christopher C Niewczas Monika A MA Israelsen William J WJ Tinsley Liane L Stillman Isaac E IE Amenta Peter S PS Feener Edward P EP Vander Heiden Matthew G MG Stanton Robert C RC King George L GL

Nature medicine 20170424 6

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, pyruv ...[more]

PMID: 28436957

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Project description:Purpose: PKM2-mediated metabolic switch to aerobic glycolysis plays a critical role in promoting cell survival and proliferation. However, little is known about the function of intestinal epithelial PKM2 in intestinal homeostasis. Here we investigated whether and how intestinal epithelial PKM2 modulates the morphology and function of the adult intestine in experimental murine colitis. Methods: Colonoscopic biopsies from the Crohn’s disease (CD) and ulcerative colitis (UC) patients (10 each) were analyzed for PKM2 expression. We also generated intestinal epithelial-specific Pkm2 knockout mice and employed them to examine PKM2 function. Mouse intestinal inflammation was induced with dextran sulfate sodium (DSS) in drinking water. Disease phenotypes were investigated by mouse survival, body weight, colon length and analysis of immune cell infiltration in colon, intestinal epithelial cell gene profiling and signal pathway. Results: Intestinal epithelial PKM2 level in UC and CD patients was significantly decreased compared to that from non-inflamed intestinal epithelium. Similar reduction of intestinal epithelial PKM2 was observed in mice with experimental colitis. Supporting the notion that PKM2 serves as a safeguard against colitis, intestinal epithelial-specific Pkm2-deficient (Pkm2-/-) mice displayed a severer intestinal inflammation, companying with shortened colon, disruption of epithelial tight junction, higher permeability, elevation of inflammatory cytokines and immune cell infiltration, compared with wild-type mice. Gene profiling and western blot analysis indicated that cell survival signaling, particularly the Akt/β-catenin pathways, were downregulated in Pkm2-/- mice. Functional assay using mouse primary colonic epithelial cells confirmed that Pkm2 reduction decreased proliferation and migration of epithelial cells, while enhanced expression of Pkm2 was associated with increased transcriptional activity of β-catenin. Moreover, increasing mouse intestinal epithelial Pkm2 expression via delivery of Pkm2-expressing plasmid attenuated DSS-induced experimental colitis. Conclusions: Intestinal epithelial PKM2, through activating Wnt/β-catenin signaling, induces a strong proliferative and migratory response that increases cell survival and wound healing under colitic condition.

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