Downregulation of CXCL16/ADAM10 axis by Simvastatin attenuates tacrolimus-induced tubulointerstitial fibrosis.

Tacrolimus (TAC), a widely used immunosuppressive agent, is associated with significant nephrotoxicity characterized by renal inflammation and fibrosis. Simvastatin (SIM), beyond its lipid-lowering effects, exhibits pleiotropic anti-inflammatory and anti-fibrotic properties. This study aimed to explore the protective effect of SIM against TAC-induced renal injury, with a focus on the potential involvement of the CXCL16/ADAM10 signaling axis. Adult male Wistar rats were divided into four groups (n = 10 per group): control, SIM-treated (SIM; 10 mg/kg/day), TAC-treated (TAC; 2 mg/kg/day), and SIM + TAC-treated. All medications were given orally for 28 days. Hematological indices, renal function parameters, and lipid profile were assessed. Histopathological evaluation and immunofluorescence analysis of CXCL16, ADAM10, fibronectin and TGF-β were performed. TAC administration resulted in significant renal dysfunction, dyslipidemia, and marked histopathological alterations, accompanied by upregulation of CXCL16, ADAM10, and fibrotic markers. Conversely, co-administration of SIM and TAC improved renal function, attenuated lipid abnormalities, and preserved renal architecture. These effects were associated with decreased the expression of CXCL16, ADAM10, TGF-β and fibronectin. SIM demonstrates significant kidney-protective properties against TAC-induced renal injury, potentially involving modulation of the CXCL16/ADAM10 signaling pathway. These findings indicate that SIM could be a beneficial supplementary treatment to alleviate the serious kidney-damaging effects associated with TAC.