title: Genetic targeting or pharmacologic inhibition of NADPH oxidase nox4 provides renoprotection in long-term diabetic nephropathy.
abstract: Diabetic nephropathy may occur, in part, as a result of intrarenal oxidative stress. NADPH oxidases comprise the only known dedicated reactive oxygen species (ROS)-forming enzyme family. In the rodent kidney, three isoforms of the catalytic subunit of NADPH oxidase are expressed (Nox1, Nox2, and Nox4). Here we show that Nox4 is the main source of renal ROS in a mouse model of diabetic nephropathy induced by streptozotocin administration in ApoE(-/-) mice. Deletion of Nox4, but not of Nox1, resulted in renal protection from glomerular injury as evidenced by attenuated albuminuria, preserved structure, reduced glomerular accumulation of extracellular matrix proteins, attenuated glomerular macrophage infiltration, and reduced renal expression of monocyte chemoattractant protein-1 and NF-κB in streptozotocin-induced diabetic ApoE(-/-) mice. Importantly, administration of the most specific Nox1/4 inhibitor, GKT137831, replicated these renoprotective effects of Nox4 deletion. In human podocytes, silencing of the Nox4 gene resulted in reduced production of ROS and downregulation of proinflammatory and profibrotic markers that are implicated in diabetic nephropathy. Collectively, these results identify Nox4 as a key source of ROS responsible for kidney injury in diabetes and provide proof of principle for an innovative small molecule approach to treat and/or prevent chronic kidney failure.
authors: Diabetic Complications Division, Juvenile Diabetes Research Foundation Danielle Alberti Memorial Centre for Diabetic Complications, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; Department of Medicine, Monash University, Melbourne, Victoria, Australia;
authors: Jay C
authors: JC
authors: Jha
authors: Diabetic Complications Division, Juvenile Diabetes Research Foundation Danielle Alberti Memorial Centre for Diabetic Complications, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia;
authors: Stephen P
authors: SP
authors: Gray
authors: Diabetic Complications Division, Juvenile Diabetes Research Foundation Danielle Alberti Memorial Centre for Diabetic Complications, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia;
authors: David
authors: D
authors: Barit
authors: Human Epigenetics Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia;
authors: Jun
authors: J
authors: Okabe
authors: Human Epigenetics Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia;
authors: Assam
authors: A
authors: El-Osta
authors: Diabetic Complications Division, Juvenile Diabetes Research Foundation Danielle Alberti Memorial Centre for Diabetic Complications, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan;
authors: Tamehachi
authors: T
authors: Namikoshi
authors: Diabetic Complications Division, Juvenile Diabetes Research Foundation Danielle Alberti Memorial Centre for Diabetic Complications, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia;
authors: Vicki
authors: V
authors: Thallas-Bonke
authors: Department of Pharmacology, Cardiovascular Research Institute Maastricht, Faculty of Medicine, Health & Life Science, Maastricht University, Maastricht, The Netherlands;
authors: Kirstin
authors: K
authors: Wingler
authors: Genkyotex SA, Geneva, Switzerland;
authors: Cedric
authors: C
authors: Szyndralewiez
authors: Genkyotex SA, Geneva, Switzerland;
authors: Freddy
authors: F
authors: Heitz
authors: Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors: Rhian M
authors: RM
authors: Touyz
authors: Diabetic Complications Division, Juvenile Diabetes Research Foundation Danielle Alberti Memorial Centre for Diabetic Complications, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; Department of Medicine, Monash University, Melbourne, Victoria, Australia;
authors: Mark E
authors: ME
authors: Cooper
authors: Department of Pharmacology, Cardiovascular Research Institute Maastricht, Faculty of Medicine, Health & Life Science, Maastricht University, Maastricht, The Netherlands;
authors: Harald H H W
authors: HH
authors: Schmidt
authors: Diabetic Complications Division, Juvenile Diabetes Research Foundation Danielle Alberti Memorial Centre for Diabetic Complications, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; Department of Medicine, Monash University, Melbourne, Victoria, Australia; karin.jandeleit-dahm@bakeridi.edu.au.
authors: Karin A
authors: KA
authors: Jandeleit-Dahm
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D020868:Gene Silencing; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050199:Podocytes / Q000166:cytology / Q000201:enzymology*; D011720:Pyrazoles / Q000494:pharmacology*; D047069:Pyrazolones; D011725:Pyridines / Q000494:pharmacology*; D011728:Pyridones; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; 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; C402799:NOX1 protein, human; C000614711:NOX1 protein, mouse; C498910:NOX4 protein, human; C422943:Nox4 protein, mouse; D005947:Glucose