Targeting CXCR2 ameliorated tacrolimus-induced nephrotoxicity by alleviating overactivation of PI3K/AKT/mTOR pathway and calcium overload

Objectives: The purposes of this study were to (i) verify the role of CXCR2 in tacrolimus-induced nephrotoxicity, (ii) explore the specific mechanism of CXCR2-mediated tacrolimus nephrotoxicity, and (iii) target the antagonism of CXCR2 and provide a potential target for the treatment of tacrolimus-induced nephrotoxicity in children. Methods: CXCR2 knockout (CXCR2-KO) mice were used to evaluate the role of CXCR2 in tacrolimus-induced nephrotoxicity. Wistar rats were used to explore the underlying mechanism. Results: In the knockout mice, compared with N-WT group, the renal function index was deteriorative (P < 0.01), the degree of renal fibrosis was aggravated (P < 0.01), the pathological expression of E-cadherin (P < 0.01) and α-SMA (P < 0.01) were occurred in T-WT group. Inversely, compared with T-WT group, the above indicators were improved in T-KO group (P < 0.01). In wistar rats, compared with N group, the renal function index was deteriorative (P < 0.05 or P < 0.01), fibrosis and calcium overload occurred (P < 0.01), CXCL2-CXCR2 was activated (P < 0.05), and meanwhile PI3K/AKT/mTOR pathway was activated (P < 0.05 or P < 0.01) in T group. Inversely, compared with T group, the above indicators were reversed in C group (P < 0.05 or P < 0.01). Conclusion: The present study was firstly to report that CXCL2-CXCR2 activated PI3K/AKT/mTOR pathway and calcium overload in tacrolimus-induced nephrotoxicity, and targeting CXCR2 could inhibit the progression of tacrolimus-induced nephrotoxicity.