title: Olmesartan protects against oxidative stress possibly through the Nrf2 signaling pathway and inhibits inflammation in daunorubicin-induced nephrotoxicity in rats.
abstract: Anthracycline anticancer drug daunorubicin (DNR) can induce chronic nephrotoxicity, which is believed to be based on oxidative injury. Olmesartan has significant blood pressure lowering effect via modulating renin-angiotensin system although its mechanism of action in DNR-induced renal injury is largely unknown. Transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important regulator of cellular oxidative stress. This study examined the role of Nrf2 in olmesartan-mediated antioxidant effects in DNR induced kidney cells. In addition, key factors involved in promoting inflammation and oxidative stress were studied. Sprague-Dawley rats were treated with a cumulative dose of 9 mg/kg DNR (i.v.). Olmesartan was administered orally every day for 6 weeks. DNR treated rats showed nephrotoxicity as evidenced by worsening renal function, which was evaluated by measuring total cholesterol, triglyceride levels in kidney tissue and histopathological approaches; treatment with olmesartan reversed these changes. Furthermore, olmesartan treatment down-regulated phospho-MAPKAPK-2, caspase-12, p47(phox), p67(phox), upregulated renal expression of PPAR-γ, Bcl-xL, glutathione peroxidase and Nrf2. Furthermore, olmesartan down-regulated matrix metalloproteinase-2 and angiotensin II type I receptor expression in the kidney. In conclusion, the result demonstrated that angiotensin II and oxidative stress play a key role in DNR-induced nephrotoxicity. The present results indicated that olmesartan protects against oxidative stress, which may be possibly via the induction of Nrf2 signaling pathways.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Vengadeshprabhu Karuppa
authors.initials: VK
authors.lastname: Gounder
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Somasundaram
authors.initials: S
authors.lastname: Arumugam
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Wawaimuli
authors.initials: W
authors.lastname: Arozal
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Rajarajan A
authors.initials: RA
authors.lastname: Thandavarayan
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Vigneshwaran
authors.initials: V
authors.lastname: Pitchaimani
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Meilei
authors.initials: M
authors.lastname: Harima
authors.affiliation: Department of Gastroenterology, Niigata University Graduate School of Medical and Dental Sciences, Niigata City 951-8510, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nomoto
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan. Electronic address: watanabe@nupals.ac.jp.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic; D001806:Blood Urea Nitrogen; D002784:Cholesterol / Q000097:blood; D003404:Creatinine / Q000097:blood; D003630:Daunorubicin; D005979:Glutathione Peroxidase / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000893:Anti-Inflammatory Agents; D000903:Antibiotics, Antineoplastic; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014280:Triglycerides; C437965:olmesartan; D002784:Cholesterol; D003404:Creatinine; D005979:Glutathione Peroxidase; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D003630:Daunorubicin
keywords: Angiotensin II type I receptor; Chronic nephrotoxicity; Daunorubicin; Nuclear factor-erythroid 2-related factor 2; Olmesartan; Oxidative stress