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Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes.
- Source :
-
Clinical science (London, England : 1979) [Clin Sci (Lond)] 2013 Feb; Vol. 124 (3), pp. 191-202. - Publication Year :
- 2013
-
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.
- Subjects :
- Albuminuria prevention & control
Albuminuria urine
Animals
Blood Glucose analysis
Blood Pressure drug effects
Blotting, Western
Body Weight drug effects
Diabetes Mellitus, Type 2 blood
Diabetes Mellitus, Type 2 urine
Diabetic Nephropathies etiology
Diabetic Nephropathies physiopathology
Disease Models, Animal
Gene Expression Regulation, Enzymologic drug effects
Kidney drug effects
Kidney metabolism
Kidney pathology
Male
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinases metabolism
NADH, NADPH Oxidoreductases antagonists & inhibitors
NADH, NADPH Oxidoreductases genetics
NADH, NADPH Oxidoreductases metabolism
NADPH Oxidase 1
NADPH Oxidase 4
NADPH Oxidases genetics
NADPH Oxidases metabolism
Reverse Transcriptase Polymerase Chain Reaction
Superoxide Dismutase genetics
Superoxide Dismutase metabolism
Superoxide Dismutase-1
Thiobarbituric Acid Reactive Substances analysis
Transforming Growth Factor beta metabolism
Vascular Cell Adhesion Molecule-1 metabolism
Diabetes Mellitus, Type 2 complications
Diabetic Nephropathies prevention & control
NADPH Oxidases antagonists & inhibitors
Pyrazoles pharmacology
Pyridones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1470-8736
- Volume :
- 124
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Clinical science (London, England : 1979)
- Publication Type :
- Academic Journal
- Accession number :
- 22920224
- Full Text :
- https://doi.org/10.1042/CS20120330