TY - JOUR
T1 - Olmesartan protects against oxidative stress possibly through the Nrf2 signaling pathway and inhibits inflammation in daunorubicin-induced nephrotoxicity in rats
AU - Gounder, Vengadeshprabhu Karuppa
AU - Arumugam, Somasundaram
AU - Arozal, Wawaimuli
AU - Thandavarayan, Rajarajan A.
AU - Pitchaimani, Vigneshwaran
AU - Harima, Meilei
AU - Suzuki, Kenji
AU - Nomoto, Mayumi
AU - Watanabe, Kenichi
N1 - Funding Information:
This research was supported by a Yujin Memorial Grant, Ministry of Education, Culture, Sports and Technology of Japan and by a grant from the Promotion and Mutual Aid Corporation for Private Schools, Japan .
PY - 2014/2
Y1 - 2014/2
N2 - 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, p47phox, p67phox, 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.
AB - 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, p47phox, p67phox, 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.
KW - Angiotensin II type I receptor
KW - Chronic nephrotoxicity
KW - Daunorubicin
KW - Nuclear factor-erythroid 2-related factor 2
KW - Olmesartan
KW - Oxidative stress
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U2 - 10.1016/j.intimp.2013.11.018
DO - 10.1016/j.intimp.2013.11.018
M3 - Article
C2 - 24291173
AN - SCOPUS:84891678367
SN - 1567-5769
VL - 18
SP - 282
EP - 289
JO - International Immunopharmacology
JF - International Immunopharmacology
IS - 2
ER -