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Diabetes. 2016 May;65(5):1387-97. doi: 10.2337/db15-0519. Epub 2016 Feb 23.

HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice.

Author information

1
Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX.
2
Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX Audie L. Murphy Memorial VA Hospital Division, South Texas Veterans Health Care System, San Antonio, TX.
3
Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX Audie L. Murphy Memorial VA Hospital Division, South Texas Veterans Health Care System, San Antonio, TX block@uthscsa.edu.

Abstract

Hypoxia-inducible factor (HIF)-1 mediates hypoxia- and chronic kidney disease-induced fibrotic events. Here, we assessed whether HIF-1 blockade attenuates the manifestations of diabetic nephropathy in a type 1 diabetic animal model, OVE26. YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole], an HIF-1 inhibitor, reduced whole kidney glomerular hypertrophy, mesangial matrix expansion, extracellular matrix accumulation, and urinary albumin excretion as well as NOX4 protein expression and NADPH-dependent reactive oxygen species production, while blood glucose levels remained unchanged. The role of NOX oxidases in HIF-1-mediated extracellular matrix accumulation was explored in vitro using glomerular mesangial cells. Through a series of genetic silencing and adenoviral overexpression studies, we have defined GLUT1 as a critical downstream target of HIF-1α mediating high glucose-induced matrix expression through the NADPH oxidase isoform, NOX4. Together, our data suggest that pharmacological inhibition of HIF-1 may improve clinical manifestations of diabetic nephropathy.

PMID:
26908870
PMCID:
PMC4839204
DOI:
10.2337/db15-0519
[Indexed for MEDLINE]
Free PMC Article

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