title: Melatonin nephroprotective action in Zucker diabetic fatty rats involves its inhibitory effect on NADPH oxidase.
abstract: Excessive activity of NADPH oxidase (Nox) is considered to be of importance for the progress of diabetic nephropathy. The aim of the study was to elucidate the effect of melatonin, known for its nephroprotective properties, on Nox activity under diabetic conditions. The experiments were performed on three groups of animals: (i) untreated lean (?/+) Zucker diabetic fatty (ZDF) rats; (ii) untreated obese diabetic (fa/fa) ZDF rats; and (iii) ZDF fa/fa rats treated with melatonin (20 mg/L) in drinking water. Urinary albumin excretion was measured weekly. After 4 wk of the treatment, the following parameters were determined in kidney cortex: Nox activity, expression of subunits of the enzyme, their phosphorylation and subcellular distribution. Histological studies were also performed. Compared to ?/+ controls, ZDF fa/fa rats exhibited increased renal Nox activity, augmented expression of Nox4 and p47(phox) subunits, elevated level of p47(phox) phosphorylation, and enlarged phospho-p47(phox) and p67(phox) content in membrane. Melatonin administration to ZDF fa/fa rats resulted in the improvement of renal functions, as manifested by considerable attenuation of albuminuria and some amelioration of structural abnormalities. The treatment turned out to nearly normalize Nox activity, which was accompanied by considerably lowered expression and diminished membrane distribution of regulatory subunits, that is, phospho-p47(phox) and p67(phox) . Thus, it is concluded that: (i) melatonin beneficial action against diabetic nephropathy involves attenuation of the excessive activity of Nox; and (ii) the mechanism of melatonin inhibitory effect on Nox is based on the mitigation of expression and membrane translocation of its regulatory subunits.
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Winiarska
authors.affiliation: Department of Biochemistry, Faculty of Agriculture and Biology, Warsaw University of Life Sciences - SGGW, Warsaw, Poland.
authors.forename: Jolanta M
authors.initials: JM
authors.lastname: Dzik
authors.affiliation: Department of Biochemistry, Faculty of Agriculture and Biology, Warsaw University of Life Sciences - SGGW, Warsaw, Poland.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Labudda
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Warsaw, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Focht
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Warsaw, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Sierakowski
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Warsaw, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Owczarek
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Warsaw, Poland.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Komorowski
authors.affiliation: Department of Exotic, Laboratory and Non-domesticated Animals Pathology, Faculty of Veterinary Medicine, Warsaw University of Life Sciences - SGGW, Warsaw, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Bielecki
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000201:enzymology* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D008550:Melatonin / Q000494:pharmacology*; D009247:NADH, NADPH Oxidoreductases / Q000096:biosynthesis*; D019255:NADPH Oxidases / Q000096:biosynthesis*; D051381:Rats; D011924:Rats, Zucker
chemical_list: D009247:NADH, NADPH Oxidoreductases; C583073:NCF2 protein, rat; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D008550:Melatonin
keywords: NADPH oxidase; Zucker diabetic fatty rat; diabetes; melatonin; nephropathy