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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2016
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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. |
format | Online Article Text |
id | pubmed-4839204 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
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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