Arsenic trioxide and curcumin attenuate cisplatin-induced renal fibrosis in rats through targeting Hedgehog signaling

Renal fibrosis is a progressive process resulting from a sustained injury that may ultimately cause renal failure. Cisplatin is an antitumor drug that induces renal injury and nephrotoxicity and is widely employed as a model for acute and chronic renal injury. Several signaling pathways are implicated in fibrogenic cell activation among which is Hedgehog (Hh) signaling. We here investigated the effects of arsenic trioxide (Ars) and curcumin in ameliorating cisplatin-induced kidney fibrosis via regulating Hh signaling. Cisplatin (4.5 mg/kg) was administered in Sprague-Dawley rats for two consecutive days and renal fibrosis was induced after 21 days. Once renal fibrosis was confirmed, Ars (3.5 mg/kg/day, orally) and curcumin (200 mg/kg/day, orally) were administered daily for another 21 days. Ars and curcumin corrected kidney function markers as creatinine clearance and urea nitrogen. Both agents ameliorated fibrosis as shown by lowered TGF-beta 1 mRNA levels, alpha-SMA protein levels, and hydroxylproline content. Cisplatin-activated Hh signaling which was blocked by both Ars and curcumin as demonstrated by decreased mRNA levels of Shh, Smo, and Ptch and suppressed renal Gli1 and Gli2 protein levels. Our results indicate new therapeutic roles for Ars and curcumin and suggest that blocking Hh signaling may be a promising approach for alleviating renal fibrosis. Symbols indicate alpha-SMA, alpha-smooth muscle actin; TGF-beta, transforming growth factor-beta; Ptch, patched; Smo, smoothened; Shh, sonic hedgehog; Ihh, Indian hedgehog; Dhh, desert hedgehog; and SUFU, suppressor of fused.