title: Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes.
abstract: 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.
authors.affiliation: *Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Mona
authors.initials: M
authors.lastname: Sedeek
authors.forename: Alex
authors.initials: A
authors.lastname: Gutsol
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Montezano
authors.forename: Dylan
authors.initials: D
authors.lastname: Burger
authors.forename: Aurelie
authors.initials: A
authors.lastname: Nguyen Dinh Cat
authors.forename: Chris R J
authors.initials: CR
authors.lastname: Kennedy
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Burns
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Karin
authors.initials: K
authors.lastname: Jandeleit-Dahm
authors.forename: Patrick
authors.initials: P
authors.lastname: Page
authors.forename: Cedric
authors.initials: C
authors.lastname: Szyndralewiez
authors.forename: Freddy
authors.initials: F
authors.lastname: Heitz
authors.forename: Richard L
authors.initials: RL
authors.lastname: Hebert
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
mesh_terms: D000419:Albuminuria / Q000517:prevention & control / Q000652:urine; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000652:urine; D003928:Diabetic Nephropathies / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; 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; D011720:Pyrazoles / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C554850:2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo(4,3-c)pyridine-3,6(2H,5H)-dione; D001786:Blood Glucose; D011720:Pyrazoles; D011728:Pyridones; D017392:Thiobarbituric Acid Reactive Substances; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; C422943:Nox4 protein, mouse; D020928:Mitogen-Activated Protein Kinases