HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice
| Autor: | William E. Friedrichs, Bijaya K. Nayak, Jeffrey L. Barnes, Mandakini Patel, Rita C. Cavaglierii, Karthigayan Shanmugasundaram, Karen Block |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Complications Endocrinology Diabetes and Metabolism Kidney Antioxidants Diabetic nephropathy 0302 clinical medicine Diabetic Nephropathies Renal Insufficiency Glucose Transporter Type 1 NADPH oxidase biology NOX4 Glomerular Hypertrophy Recombinant Proteins Extracellular Matrix 3. Good health medicine.anatomical_structure NADPH Oxidase 4 030220 oncology & carcinogenesis Mesangial Cells RNA Interference medicine.medical_specialty Indazoles Glomerular Mesangial Cell Mice Transgenic Cell Line 03 medical and health sciences Internal medicine Internal Medicine medicine Renal fibrosis Animals Hypoglycemic Agents business.industry NADPH Oxidases Kidney metabolism Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Fibrosis Hypoglycemia Oxidative Stress Diabetes Mellitus Type 1 030104 developmental biology Endocrinology Gene Expression Regulation Hyperglycemia Immunology biology.protein business |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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