title: Combination therapy with losartan and pioglitazone additively reduces renal oxidative and nitrative stress induced by chronic high fat, sucrose, and sodium intake.
abstract: We recently showed that combination therapy with losartan and pioglitazone provided synergistic effects compared with monotherapy in improving lesions of renal structure and function in Sprague-Dawley rats fed with a high-fat, high-sodium diet and 20% sucrose solution. This study was designed to explore the underlying mechanisms of additive renoprotection provided by combination therapy. Losartan, pioglitazone, and their combination were orally administered for 8 weeks. The increased level of renal malondialdehyde and expression of nicotinamide adenine dinucleotide phosphate oxidase subunit p47(phox) and nitrotyrosine as well as the decreased total superoxide dismutase activity and copper, zinc-superoxide dismutase expression were tangible evidence for the presence of oxidative and nitrative stress in the kidney of model rats. Treatment with both drugs, individually and in combination, improved these abnormal changes. Combination therapy showed synergistic effects in reducing malondialdehyde level, p47(phox), and nitrotyrosine expression to almost the normal level compared with monotherapy. All these results suggest that the additive renoprotection provided by combination therapy might be attributed to a further reduction of oxidative and nitrative stress.
authors.affiliation: Department of Pharmacology, Third-Grade Pharmacology Laboratory of State Administration of Traditional Chinese Medicine, Wannan Medical College, Anhui, Wuhu 241002, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Kong
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hai-bing
authors.initials: HB
authors.lastname: Wu
authors.forename: Fang-xia
authors.initials: FX
authors.lastname: Li
authors.forename: Dao-you
authors.initials: DY
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Su
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat; D019422:Dietary Sucrose; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D015538:Nitrosation / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012982:Sodium, Dietary; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D019422:Dietary Sucrose; D012333:RNA, Messenger; D012982:Sodium, Dietary; D045162:Thiazolidinediones; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D019808:Losartan; D000077205:Pioglitazone