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The Histone Methyltransferase Enzyme Enhancer of Zeste Homolog 2 Protects against Podocyte Oxidative Stress and Renal Injury in Diabetes

Lookup NU author(s): Dr Kathryn White


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Epigenetic regulation of oxidative stress is emerging as a critical mediator of diabetic nephropathy. In diabetes, oxidative damage occurs when there is an imbalance between reactive oxygen species generation and enzymatic antioxidant repair. Here, we investigated the function of the histone methyltransferase enzyme enhancer of zeste homolog 2 (EZH2) in attenuating oxidative injury in podocytes, focusing on its regulation of the endogenous antioxidant inhibitor thioredoxin interacting protein (TxnIP). Pharmacologic or genetic depletion of EZH2 augmented TxnIP expression and oxidative stress in podocytes cultured under high-glucose conditions. Conversely, EZH2 upregulation through inhibition of its regulatory microRNA, microRNA-101, downregulated TxnIP and attenuated oxidative stress. In diabetic rats, depletion of EZH2 decreased histone 3 lysine 27 trimethylation (H3K27me3), increased glomerular TxnIP expression, induced podocyte injury, and augmented oxidative stress and proteinuria. Chromatin immunoprecipitation sequencing revealed H3K27me3 enrichment at the promoter of the transcription factor Pax6, which was upregulated on EZH2 depletion and bound to the TxnIP promoter, controlling expression of its gene product. In high glucose exposed podocytes and the kidneys of diabetic rats, the lower EZH2 expression detected coincided with upregulation of Pax6 and TxnIP. Finally, in a gene expression array, TxnIP was among seven of 30,854 genes upregulated by high glucose, EZH2 depletion, and the combination thereof. Thus, EZH2 represses the transcription factor Pax6, which controls expression of the antioxidant inhibitor TxnIP, and in diabetes, downregulation of EZH2 promotes oxidative stress. These findings expand the extent to which epigenetic processes affect the diabetic kidney to include antioxidant repair.

Publication metadata

Author(s): Siddiqi FS, Majumder S, Thai K, Abdalla M, Hu PZ, Advani SL, White KE, Bowskill BB, Guarna G, dos Santos CC, Connelly KA, Advani A

Publication type: Article

Publication status: Published

Journal: Journal of the American Society of Nephrology

Year: 2016

Volume: 27

Issue: 7

Pages: 2021-2034

Print publication date: 01/07/2016

Online publication date: 03/11/2015

Acceptance date: 22/09/2015

ISSN (print): 1046-6673

ISSN (electronic): 1533-3450

Publisher: American Society of Nephrology


DOI: 10.1681/ASN.2014090898


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Funder referenceFunder name
Canadian Diabetes Association Post-Doctoral Fellowship
Canadian Institutes of Health Research
Charles Hollenberg Summer Studentship from the Banting and Best Diabetes Centre
Kidney Foundation of Canada
Banting and Best Diabetes Centre Fellowship in Diabetes Care - Eli Lilly Canada
Clinician Scientist Award from the Canadian Diabetes Association
Endocrine Society
Ontario Genomics Institute
Reuben and Helene Dennis Scholar Award from the Banting and Best Diabetes Centre
OG-3-14-4502Canadian Diabetes Association