期刊
INTERNATIONAL IMMUNOPHARMACOLOGY
卷 18, 期 2, 页码 282-289出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.intimp.2013.11.018
关键词
Daunorubicin; Olmesartan; Oxidative stress; Chronic nephrotoxicity; Nuclear factor-erythroid 2-related factor 2; Angiotensin II type I receptor
资金
- Yujin Memorial Grant, Ministry of Education, Culture, Sports and Technology of Japan
- Promotion and Mutual Aid Corporation for Private Schools, Japan
- Grants-in-Aid for Scientific Research [24590938] Funding Source: KAKEN
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-gamma, 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. (C) 2013 Elsevier B.V. All rights reserved.
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