Acylated ghrelin protects against doxorubicin-induced nephropathy by activating silent information regulator 1.

This study investigated the nephroprotective role of acylated ghrelin (AG) against DOX-induced nephropathy and examined whether the protection involves silent information regulator 1 (SIRT1). Rats were divided into control, control + AG, DOX, DOX + AG, DOX + AG + [D-Lys3]-GHRP-6 (a ghrelin receptor antagonist), and DOX + AG + EX-527 (a sirt1 inhibitor). DOX was given over the first 2 weeks. AG (10 ng/kg) and both inhibitors were given as 3 doses/wk for 5 weeks. AG improved the structure and the function of the kidneys; down-regulated the renal expression of TGF-β1, collagen 1A1 and α-SMA; and inhibited the renal collagen deposition in the kidneys of DOX-treated rats. Concomitantly, it reduced the renal levels of ROS, MDA, TNF-α, and IL-6 and protein levels of cytochrome-c, TGF-β1, Smad3 and α-SMA in these rats. In both the control and DOX-treated rats, AG significantly increased the renal levels of SOD and GSH, decreased the expression of cleaved caspase-3 and Bax, increased the total levels and the nuclear activity of SIRT1 and reduced the deacetylation of p53, NF-κB and FOXO-31. All the effects were abolished by the concurrent administration of EX-527 and [D-Lys3]-GHRP-6. In conclusion, AG prevents DOX-induced nephropathy in SIRT1 and GSHRa1-dependent mechanism.