Angiotensin II receptor blockade alleviates calcineurin inhibitor nephrotoxicity by restoring cyclooxygenase 2 expression in kidney cortex
Angiotensin II receptor blockade alleviates calcineurin inhibitor nephrotoxicity by restoring cyclooxygenase 2 expression in kidney cortex
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DOI：
10.1111/apha.13612
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发表时间：
2021-01-18
影响因子：
6.3
通讯作者：
Mutig, Kerim
中科院分区：
文献类型：
--
作者：
Hu, Junda;Xu, Yan;Mutig, Kerim
目的：实体器官移植后使用钙调神经磷酸酶抑制剂（如环孢素 A (CsA)）进行免疫抑制通常会受到肾脏副作用的限制。 CsA 引起的肾小球滤过率和钠潴留恶化可能与抑制环氧合酶 2 (COX-2) 和刺激肾素生物合成导致的肾小球旁失调有关。我们测试了 CsA 诱导的 COX-2 抑制是否由肾素血管紧张素系统 (RAS) 过度活跃引起，以及 RAS 抑制是否可以减轻相关副作用。方法：大鼠急性（3 天）或慢性（3 周）接受 CsA、RAS 抑制剂坎地沙坦或 COX-2 抑制剂塞来昔布。在培养的致密斑细胞中研究了 CsA 和 RAS 对 COX-2 介导作用的分子途径。结果：培养细胞中药理学或 siRNA 介导的钙调磷酸酶抑制通过 p38 丝裂原激活蛋白激酶和 NF-kB 信号传导增强了 COX-2 的表达，而血管紧张素 II 消除了这些作用。对大鼠进行急性和慢性 CsA 给药会导致 RAS 激活，同时皮质 COX-2 表达、肌酐清除率和钠排泄分数降低。对主要远端盐转运蛋白 NKCC2 和 NCC 的评估显示，它们在 CsA 上的激活磷酸化水平增加。联合坎地沙坦治疗可显着减弱这些影响，并长期使 COX-2 表达和肾功能参数完全正常化。塞来昔布阻止了坎地沙坦诱导的肌酐清除率和钠排泄的改善。结论：RAS 激活导致 CsA 抑制肾小球旁 COX-2，这超越了钙调神经磷酸酶抑制的细胞自主、COX-2 刺激作用。血管紧张素 II 拮抗作用通过 COX-2 依赖性的肌酐清除率和钠排泄正常化来减轻 CsA 肾毒性。
Aim: The use of calcineurin inhibitors such as cyclosporine A (CsA) for immunosuppression after solid organ transplantation is commonly limited by renal side effects. CsA-induced deterioration of glomerular filtration rate and sodium retention may be related to juxtaglomerular dysregulation as a result of suppressed cyclooxygenase 2 (COX-2) and stimulated renin biosynthesis. We tested whether CsA-induced COX-2 suppression is caused by hyperactive renin-angiotensin system (RAS) and whether RAS inhibition may alleviate the related side effects.Methods: Rats received CsA, the RAS inhibitor candesartan, or the COX-2 inhibitor celecoxib acutely (3 days) or chronically (3 weeks). Molecular pathways mediating effects of CsA and RAS on COX-2 were studied in cultured macula densa cells.Results: Pharmacological or siRNA-mediated calcineurin inhibition in cultured cells enhanced COX-2 expression via p38 mitogen-activated protein kinase and NF-kB signalling, whereas angiotensin II abolished these effects. Acute and chronic CsA administration to rats led to RAS activation along with reduced cortical COX-2 expression, creatinine clearance and fractional sodium excretion. Evaluation of major distal salt transporters, NKCC2 and NCC, showed increased levels of their activating phosphorylation upon CsA. Concomitant candesartan treatment blunted these effects acutely and completely normalized the COX-2 expression and renal functional parameters at long term. Celecoxib prevented the candesartan-induced improvements of creatinine clearance and sodium excretion.Conclusion: Suppression of juxtaglomerular COX-2 upon CsA results from RAS activation, which overrides the cell-autonomous, COX-2-stimulatory effects of calcineurin inhibition. Angiotensin II antagonism alleviates CsA nephrotoxicity via the COX-2-dependent normalization of creatinine clearance and sodium excretion.