title: Targeting NADPH oxidase with a novel dual Nox1/Nox4 inhibitor attenuates renal pathology in type 1 diabetes.
abstract: Reactive oxygen species (ROS) generated by Nox NADPH oxidases may play a critical role in the pathogenesis of diabetic nephropathy (DN). The efficacy of the Nox1/Nox4 inhibitor GKT137831 on the manifestations of DN was studied in OVE26 mice, a model of type 1 diabetes. Starting at 4-5 mo of age, OVE26 mice were treated with GKT137831 at 10 or 40 mg/kg, once-a-day for 4 wk. At both doses, GKT137831 inhibited NADPH oxidase activity, superoxide generation, and hydrogen peroxide production in the renal cortex from diabetic mice without affecting Nox1 or Nox4 protein expression. The increased expression of fibronectin and type IV collagen was reduced in the renal cortex, including glomeruli, of diabetic mice treated with GKT137831. GKT137831 significantly reduced glomerular hypertrophy, mesangial matrix expansion, urinary albumin excretion, and podocyte loss in OVE26 mice. GKT137831 also attenuated macrophage infiltration in glomeruli and tubulointerstitium. Collectively, our data indicate that pharmacological inhibition of Nox1/4 affords broad renoprotection in mice with preexisting diabetes and established kidney disease. This study validates the relevance of targeting Nox4 and identifies GKT137831 as a promising compound for the treatment of DN in type 1 diabetes.
authors: Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas; gorin@uthscsa.edu.
authors: Yves
authors: Y
authors: Gorin
authors: Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas;
authors: Rita C
authors: RC
authors: Cavaglieri
authors: Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas;
authors: Khaled
authors: K
authors: Khazim
authors: Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas;
authors: Doug-Yoon
authors: DY
authors: Lee
authors: Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas;
authors: Francesca
authors: F
authors: Bruno
authors: Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas;
authors: Sachin
authors: S
authors: Thakur
authors: Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas; Audie Leon Murphy Memorial Hospital Division, South Texas Veterans Health Care System, San Antonio, Texas; and.
authors: Paolo
authors: P
authors: Fanti
authors: Genkyotex SA, Geneva, Switzerland.
authors: Cédric
authors: C
authors: Szyndralewiez
authors: Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas; Audie Leon Murphy Memorial Hospital Division, South Texas Veterans Health Care System, San Antonio, Texas; and.
authors: Jeffrey L
authors: JL
authors: Barnes
authors: Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas; Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas;
authors: Karen
authors: K
authors: Block
authors: Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas; Audie Leon Murphy Memorial Hospital Division, South Texas Veterans Health Care System, San Antonio, Texas; and.
authors: Hanna E
authors: HE
authors: Abboud
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D047069:Pyrazolones; D011725:Pyridines / Q000494:pharmacology*; D011728:Pyridones; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; D047069:Pyrazolones; D011725:Pyridines; D011728:Pyridones; D017382:Reactive Oxygen Species; C576694:setanaxib; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; C422943:Nox4 protein, mouse
keywords: NADPH oxidase; Nox1/Nox4 inhibitor; diabetic nephropathy
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