Rosiglitazone ameliorates cisplatin-induced renal injury in mice

Sik Lee, Won Kim, Sang-Ok Moon, Mi Jeong Sung, Duk Hoon Kim, Kyung Pyo Kang, Yong Bum Jang, Jung Eun Lee, Kyu Yun Jang, Sung Kwang Park
2006 Nephrology, Dialysis and Transplantation  
Background. Inflammatory mechanisms may play an important role in the pathogenesis of cisplatin nephrotoxicity. Agonists of the peroxisome proliferatoractivated receptor-g (PPARg), such as rosiglitazone, have been recently demonstrated to regulate inflammation by modulating the production of inflammatory mediators and adhesion molecules. The purpose of this study was to examine the protective effects of rosiglitazone on cisplatin nephrotoxicity and to explore the mechanism of its
more » ... its renoprotection. Methods. Mice were treated with cisplatin with or without pre-treatment with rosiglitazone. Renal functions, histological findings, aquaporin 2 (AQP2) and adhesion molecule expression, macrophage infiltration and tumour necrosis factor-a (TNF-a) levels were investigated. The effect of rosiglitazone on nuclear factor (NF)-kB activity and on viability was examined using cultured human kidney (HK-2) cells. Results. Rosiglitazone significantly decreased both the damage to renal function and histological pathology after cisplatin injection. Pre-treatment with rosiglitazone reduced the systemic levels of TNF-a and downregulated adhesion molecule expression in addition to the infiltration of inflammatory cells after cisplatin administration. Rosiglitazone restored the decreased AQP2 expression after cisplatin treatment. Pretreatment with rosiglitazone blocked the phosphorylation of the p65 subunit of NF-kB in cultured HK-2 cells. Rosiglitazone had a protective effect via a PPARg-dependent pathway in cisplatin-treated HK-2 cells. Conclusion. These results showed that pre-treatment with rosiglitazone attenuates cisplatin-induced renal damage through the suppression of TNF-a overproduction and NF-kB activation. Fig. 7 . Effect of rosiglitazone on the level of TNF-a in serum following cisplatin administration. TNF-a level in serum was measured at 24, 48 and 72 h after injection, n ¼ 5 in each group. Data represent mean AE SEM from four independent experiments. Con, saline; Ros, rosiglitazone; Cis, cisplatin; Cis AE Ros, cisplatin injection with rosiglitazone. *P < 0.05 vs saline; y P < 0.05 vs cisplatin. Cis + Vehicle Con Ros
doi:10.1093/ndt/gfl194 pmid:16728429 fatcat:bdgx2o2mifdhfaxmauvy3trumy