Nox (NADPH oxidase)-derived ROS (reactive oxygen species) have been implicated in the development of diabetic nephropathy. Of the Nox isoforms in the kidney, Nox4 is important because of its renal abundance. In the present study, we tested the hypothesis that GKT136901, a Nox1/4 inhibitor, prevents the development of nephropathy in db/db (diabetic) mice. Six groups of male mice (8-week-old) were studied: (i) untreated control db/m, (ii) low-dose GKT136901-treated db/m (30 mg/kg of body weight per day), (iii) high-dose GKT136901-treated db/m (90 mg/kg of body weight per day), (iv) untreated db/db; (v) low dose GKT136901-treated db/db; and (vi) high-dose GKT136901-treated db/db. GKT136901, in chow, was administered for 16 weeks. db/db mice developed diabetes and nephropathy as evidenced by hyperglycaemia, albuminuria and renal injury (mesangial expansion, tubular dystrophy and glomerulosclerosis). GKT136901 treatment had no effect on plasma glucose or BP (blood pressure) in any of the groups. Plasma and urine TBARSs (thiobarbituric acid-reacting substances) levels, markers of systemic and renal oxidative stress, respectively, were increased in diabetic mice. Renal mRNA expression of Nox4, but not of Nox2, increased, Nox1 was barely detectable in db/db. Expression of the antioxidant enzyme SOD-1 (superoxide dismutase 1) decreased in db/db mice. Renal content of fibronectin, pro-collagen, TGFβ (transforming growth factor β) and VCAM-1 (vascular cell adhesion molecule 1) and phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) were augmented in db/db kidneys, with no change in p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase). Treatment reduced albuminuria, TBARS and renal ERK1/2 phosphorylation and preserved renal structure in diabetic mice. Our findings suggest a renoprotective effect of the Nox1/4 inhibitor, possibly through reduced oxidative damage and decreased ERK1/2 activation. These phenomena occur independently of improved glucose control, suggesting GKT136901-sensitive targets are involved in complications of diabetes rather than in the disease process.
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Research Article|
October 17 2012
Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes
Mona Sedeek;
Mona Sedeek
*Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
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Alex Gutsol;
Alex Gutsol
*Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
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Augusto C. Montezano;
Augusto C. Montezano
*Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
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Dylan Burger;
Dylan Burger
*Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
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Aurelie Nguyen Dinh Cat;
Aurelie Nguyen Dinh Cat
*Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
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Chris R. J. Kennedy;
Chris R. J. Kennedy
*Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
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Kevin D. Burns;
Kevin D. Burns
*Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
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Mark E. Cooper;
Mark E. Cooper
†Diabetic Complications Division, Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia
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Karin Jandeleit-Dahm;
Karin Jandeleit-Dahm
†Diabetic Complications Division, Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia
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Patrick Page;
Patrick Page
‡GenKyoTex S.A., Geneva, Switzerland
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Cedric Szyndralewiez;
Cedric Szyndralewiez
‡GenKyoTex S.A., Geneva, Switzerland
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Freddy Heitz;
Freddy Heitz
‡GenKyoTex S.A., Geneva, Switzerland
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Richard L. Hebert;
Richard L. Hebert
*Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
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Rhian M. Touyz
*Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
§Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, U.K.
Correspondence: Professor Rhian M. Touyz (email [email protected] or [email protected]).
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Publisher: Portland Press Ltd
Received:
June 19 2012
Revision Received:
August 06 2012
Accepted:
August 24 2012
Accepted Manuscript online:
August 24 2012
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2013 Biochemical Society
2013
Clin Sci (Lond) (2013) 124 (3): 191–202.
Article history
Received:
June 19 2012
Revision Received:
August 06 2012
Accepted:
August 24 2012
Accepted Manuscript online:
August 24 2012
Citation
Mona Sedeek, Alex Gutsol, Augusto C. Montezano, Dylan Burger, Aurelie Nguyen Dinh Cat, Chris R. J. Kennedy, Kevin D. Burns, Mark E. Cooper, Karin Jandeleit-Dahm, Patrick Page, Cedric Szyndralewiez, Freddy Heitz, Richard L. Hebert, Rhian M. Touyz; Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes. Clin Sci (Lond) 1 February 2013; 124 (3): 191–202. doi: https://doi.org/10.1042/CS20120330
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