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

Diabetes (New York, N.Y.), 2016-05, Vol.65 (5), p.1387-1397 [Peer Reviewed Journal]

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. ;Copyright American Diabetes Association May 2016 ;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. 2016 ;ISSN: 0012-1797 ;EISSN: 1939-327X ;DOI: 10.2337/db15-0519 ;PMID: 26908870 ;CODEN: DIAEAZ

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Title:
HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice
Author: Nayak, Bijaya K ; Shanmugasundaram, Karthigayan ; Friedrichs, William E ; Cavaglierii, Rita C ; Patel, Mandakini ; Barnes, Jeffrey ; Block, Karen
Subjects: Animals ; Antioxidants - pharmacology ; Antioxidants - therapeutic use ; Cell Line ; Complications ; Diabetes ; Diabetes Mellitus, Type 1 - blood ; Diabetes Mellitus, Type 1 - complications ; Diabetes Mellitus, Type 1 - drug therapy ; Diabetic Nephropathies - metabolism ; Diabetic Nephropathies - pathology ; Diabetic Nephropathies - physiopathology ; Diabetic Nephropathies - prevention & control ; Extracellular Matrix - drug effects ; Extracellular Matrix - metabolism ; Extracellular Matrix - pathology ; Fibrosis ; Gene Expression Regulation - drug effects ; Glucose Transporter Type 1 - antagonists & inhibitors ; Glucose Transporter Type 1 - genetics ; Glucose Transporter Type 1 - metabolism ; Hyperglycemia - prevention & control ; Hypoglycemia - prevention & control ; Hypoglycemic Agents - pharmacology ; Hypoglycemic Agents - therapeutic use ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors ; Hypoxia-Inducible Factor 1, alpha Subunit - genetics ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Indazoles - pharmacology ; Indazoles - therapeutic use ; Kidney - drug effects ; Kidney - metabolism ; Kidney - pathology ; Kidney - physiopathology ; Kidney diseases ; Matrix ; Mesangial Cells - cytology ; Mesangial Cells - drug effects ; Mesangial Cells - metabolism ; Mesangial Cells - pathology ; Mice, Transgenic ; NADPH Oxidase 4 ; NADPH Oxidases - antagonists & inhibitors ; NADPH Oxidases - genetics ; NADPH Oxidases - metabolism ; Oxidative Stress - drug effects ; Recombinant Proteins - chemistry ; Recombinant Proteins - metabolism ; Renal Insufficiency - complications ; Renal Insufficiency - metabolism ; Renal Insufficiency - pathology ; Renal Insufficiency - prevention & control ; RNA Interference ; Rodents
Is Part Of: Diabetes (New York, N.Y.), 2016-05, Vol.65 (5), p.1387-1397
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.
Publisher: United States: American Diabetes Association
Language: English
Identifier: ISSN: 0012-1797
EISSN: 1939-327X
DOI: 10.2337/db15-0519
PMID: 26908870
CODEN: DIAEAZ
Source: MEDLINE
PubMed Central
Alma/SFX Local Collection

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

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