title: HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice.
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.
authors.affiliation: Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Bijaya K
authors.initials: BK
authors.lastname: Nayak
authors.affiliation: Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Karthigayan
authors.initials: K
authors.lastname: Shanmugasundaram
authors.affiliation: Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: William E
authors.initials: WE
authors.lastname: Friedrichs
authors.affiliation: Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Cavaglierii
authors.affiliation: Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Mandakini
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX Audie L. Murphy Memorial VA Hospital Division, South Texas Veterans Health Care System, San Antonio, TX.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Barnes
authors.affiliation: Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX Audie L. Murphy Memorial VA Hospital Division, South Texas Veterans Health Care System, San Antonio, TX block@uthscsa.edu.
authors.forename: Karen
authors.initials: K
authors.lastname: Block
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006943:Hyperglycemia / Q000517:prevention & control; D007003:Hypoglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008822:Mice, Transgenic; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D034622:RNA Interference; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D051437:Renal Insufficiency / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control
chemical_list: D000975:Antioxidants; D051272:Glucose Transporter Type 1; C497443:Hif1a protein, mouse; D007004:Hypoglycemic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D011994:Recombinant Proteins; C495678:Slc2a1 protein, mouse; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse