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

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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

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Hypoxia-Inducible Factor 1
Fibrosis
Kidney
Diabetic Nephropathies
Extracellular Matrix
Indazoles
Mesangial Cells
NADPH Oxidase
Chronic Renal Insufficiency
NADP
Hypertrophy
Blood Glucose
Albumins
Reactive Oxygen Species
Oxidoreductases
Protein Isoforms
Animal Models
Pharmacology
Glucose
Proteins

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

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

HIF-1 mediates renal fibrosis in OVE26 type 1 diabetic mice. / Nayak, Bijaya K.; Shanmugasundaram, Karthigayan; Friedrichs, William E.; Cavaglierii, Rita C.; Patel, Mandakini; Barnes, Jeffrey; Block, Karen.

In: Diabetes, Vol. 65, No. 5, 01.05.2016, p. 1387-1397.

Research output: Contribution to journalArticle

Nayak, BK, Shanmugasundaram, K, Friedrichs, WE, Cavaglierii, RC, Patel, M, Barnes, J & Block, K 2016, 'HIF-1 mediates renal fibrosis in OVE26 type 1 diabetic mice', Diabetes, vol. 65, no. 5, pp. 1387-1397. https://doi.org/10.2337/db15-0519
Nayak BK, Shanmugasundaram K, Friedrichs WE, Cavaglierii RC, Patel M, Barnes J et al. HIF-1 mediates renal fibrosis in OVE26 type 1 diabetic mice. Diabetes. 2016 May 1;65(5):1387-1397. https://doi.org/10.2337/db15-0519
Nayak, Bijaya K. ; Shanmugasundaram, Karthigayan ; Friedrichs, William E. ; Cavaglierii, Rita C. ; Patel, Mandakini ; Barnes, Jeffrey ; Block, Karen. / HIF-1 mediates renal fibrosis in OVE26 type 1 diabetic mice. In: Diabetes. 2016 ; Vol. 65, No. 5. pp. 1387-1397.
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