靶向 CXCR2 通过减轻 PI3K/AKT/mTOR 通路的过度激活和钙超载来改善他克莫司诱导的肾毒性。
Targeting CXCR2 ameliorated tacrolimus-induced nephrotoxicity by alleviating overactivation of PI3K/AKT/mTOR pathway and calcium overload.
机构信息
School of Nursing, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
出版信息
Biomed Pharmacother. 2024 Nov;180:117526. doi: 10.1016/j.biopha.2024.117526. Epub 2024 Oct 7.
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.
目的
本研究旨在（i）验证 CXCR2 在他克莫司诱导的肾毒性中的作用，（ii）探讨 CXCR2 介导的他克莫司肾毒性的具体机制，以及（iii）靶向 CXCR2 拮抗剂为儿童他克莫司诱导的肾毒性治疗提供潜在靶点。
方法
使用 CXCR2 敲除（CXCR2-KO）小鼠来评估 CXCR2 在他克莫司诱导的肾毒性中的作用。使用 Wistar 大鼠来探讨潜在机制。
结果
在敲除小鼠中，与 N-WT 组相比，肾功能指标恶化（P < 0.01），肾纤维化程度加重（P < 0.01），E-cadherin（P < 0.01）和 α-SMA（P < 0.01）的病理表达在 T-WT 组中发生。相反，与 T-WT 组相比，T-KO 组上述指标得到改善（P < 0.01）。在 Wistar 大鼠中，与 N 组相比，肾功能指标恶化（P < 0.05 或 P < 0.01），纤维化和钙超载发生（P < 0.01），CXCL2-CXCR2 被激活（P < 0.05），同时 PI3K/AKT/mTOR 通路被激活（P < 0.05 或 P < 0.01）在 T 组中。相反，与 T 组相比，C 组上述指标得到逆转（P < 0.05 或 P < 0.01）。
结论
本研究首次报道 CXCL2-CXCR2 通过激活 PI3K/AKT/mTOR 通路和钙超载参与他克莫司诱导的肾毒性，靶向 CXCR2 可能抑制他克莫司诱导的肾毒性进展。
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