HIF-1 mediates renal fibrosis in OVE26 type 1 diabetic mice

Bijaya K. Nayak, Karthigayan Shanmugasundaram, William E. Friedrichs, Rita C. Cavaglierii, Mandakini Patel, Jeffrey Barnes, Karen Block

Research output: Contribution to journalArticle

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1387-1397
Number of pages11
JournalDiabetes
Volume65
Issue number5
DOIs
StatePublished - May 1 2016

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Nayak, B. K., Shanmugasundaram, K., Friedrichs, W. E., Cavaglierii, R. C., Patel, M., Barnes, J., & Block, K. (2016). HIF-1 mediates renal fibrosis in OVE26 type 1 diabetic mice. Diabetes, 65(5), 1387-1397. https://doi.org/10.2337/db15-0519