Evaluation of renal protective effects of inhibiting TGF-β type I receptor in a cisplatin-induced nephrotoxicity model

PURPOSE: The use of cisplatin, the first of the platinum-containing anti-cancer drugs, is limited by the development of a myriad of adverse reactions, including nephrotoxicity. We conducted this study therefore to find out whether SB-431542, potent and specific inhibitor of type I transforming growth factor-beta receptor (TGF-βR1), could prevent or attenuate kidney damage in rats, and to elucidate its possible mechanism of action. METHODS: Fifty rats were treated with cisplatin (10 mg/kg) in the presence (1 and 3 mg/kg) or absence of SB-431542. Morphological changes were assessed in kidney sections stained with H/E. Oxidative stress was evaluated in kidney homogenates by measuring malondialdehyde (MDA) and superoxide dismutase (SOD). Kidney samples were used for measurements of TGF-βR1, TGF-β1 and sCD93 by ELISA. Kidney tissue apoptosis was assessed by measuring caspase-3 activity. RESULTS: The renal protective effect of SB-431542 was confirmed by the normal appearance of renal tissue and the relatively unaffected serum creatinine and urea levels. With SB-431542, there was significantly lower renal MDA and increased SOD compared with the cisplatin group. Furthermore, in the SB-431542 group, renal TGF-βR1, TGF-β1, sCD93 and caspase-3 levels were significantly lower. CONCLUSIONS: Inhibition of TGF-βR1 provides protective effects against cisplatin-induced nephrotoxicity through several mechanisms, including attenuation of oxidative stress, inhibition of pro-inflammatory cytokines, blocking of renal fibrosis markers, and anti-apoptotic effects.