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Genetic targeting or pharmacologic inhibition of NADPH oxidase nox4 provides renoprotection in long-term diabetic nephropathy.
Jha, Jay C; Gray, Stephen P; Barit, David; Okabe, Jun; El-Osta, Assam; Namikoshi, Tamehachi; Thallas-Bonke, Vicki; Wingler, Kirstin; Szyndralewiez, Cedric; Heitz, Freddy; Touyz, Rhian M; Cooper, Mark E; Schmidt, Harald H H W; Jandeleit-Dahm, Karin A.
Afiliación
  • Jha JC; 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;
  • Gray SP; Diabetic Complications Division, Juvenile Diabetes Research Foundation Danielle Alberti Memorial Centre for Diabetic Complications, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia;
  • Barit D; Diabetic Complications Division, Juvenile Diabetes Research Foundation Danielle Alberti Memorial Centre for Diabetic Complications, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia;
  • Okabe J; Human Epigenetics Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia;
  • El-Osta A; Human Epigenetics Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia;
  • Namikoshi T; 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;
  • Thallas-Bonke V; Diabetic Complications Division, Juvenile Diabetes Research Foundation Danielle Alberti Memorial Centre for Diabetic Complications, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia;
  • Wingler K; Department of Pharmacology, Cardiovascular Research Institute Maastricht, Faculty of Medicine, Health & Life Science, Maastricht University, Maastricht, The Netherlands;
  • Szyndralewiez C; Genkyotex SA, Geneva, Switzerland;
  • Heitz F; Genkyotex SA, Geneva, Switzerland;
  • Touyz RM; Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
  • Cooper ME; 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;
  • Schmidt HH; Department of Pharmacology, Cardiovascular Research Institute Maastricht, Faculty of Medicine, Health & Life Science, Maastricht University, Maastricht, The Netherlands;
  • Jandeleit-Dahm KA; 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-dah
J Am Soc Nephrol ; 25(6): 1237-54, 2014 Jun.
Article en En | MEDLINE | ID: mdl-24511132
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Piridinas / NADPH Oxidasas / Diabetes Mellitus Experimental / Nefropatías Diabéticas / Podocitos Idioma: En Revista: J Am Soc Nephrol Asunto de la revista: NEFROLOGIA Año: 2014 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Piridinas / NADPH Oxidasas / Diabetes Mellitus Experimental / Nefropatías Diabéticas / Podocitos Idioma: En Revista: J Am Soc Nephrol Asunto de la revista: NEFROLOGIA Año: 2014 Tipo del documento: Article Pais de publicación: Estados Unidos