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

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 H...

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Autores principales: Nayak, Bijaya K., Shanmugasundaram, Karthigayan, Friedrichs, William E., Cavaglierii, Rita C., Patel, Mandakini, Barnes, Jeffrey, Block, Karen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839204/
https://www.ncbi.nlm.nih.gov/pubmed/26908870
http://dx.doi.org/10.2337/db15-0519
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author Nayak, Bijaya K.
Shanmugasundaram, Karthigayan
Friedrichs, William E.
Cavaglierii, Rita C.
Patel, Mandakini
Barnes, Jeffrey
Block, Karen
author_facet Nayak, Bijaya K.
Shanmugasundaram, Karthigayan
Friedrichs, William E.
Cavaglierii, Rita C.
Patel, Mandakini
Barnes, Jeffrey
Block, Karen
author_sort Nayak, Bijaya K.
collection PubMed
description 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.
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spelling pubmed-48392042017-05-01 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 Diabetes Complications 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. American Diabetes Association 2016-05 2016-02-23 /pmc/articles/PMC4839204/ /pubmed/26908870 http://dx.doi.org/10.2337/db15-0519 Text en © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
spellingShingle Complications
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
title HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice
title_full HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice
title_fullStr HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice
title_full_unstemmed HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice
title_short HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice
title_sort hif-1 mediates renal fibrosis in ove26 type 1 diabetic mice
topic Complications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839204/
https://www.ncbi.nlm.nih.gov/pubmed/26908870
http://dx.doi.org/10.2337/db15-0519
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