Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.
Cell Mol Life Sci. 2022 Jul 27;79(8):452. doi: 10.1007/s00018-022-04480-2.
Cisplatin is an effective chemotherapeutic drug, but it may induce both acute and chronic kidney problems. The pathogenesis of chronic kidney disease (CKD) associated with cisplatin chemotherapy remains largely unclear.
Mice and renal tubular cells were subjected to repeated low-dose cisplatin (RLDC) treatment to induce CKD and related pathological changes. The roles of endoplasmic reticulum (ER) stress, PERK, and protein kinase C-δ (PKCδ) were determined using pharmacological inhibitors and genetic manipulation.
ER stress was induced by RLDC in kidney tubular cells in both in vivo and in vitro models. ER stress inhibitors given immediately after RLDC attenuated kidney dysfunction, tubular atrophy, kidney fibrosis, and inflammation in mice. In cultured renal proximal tubular cells, inhibitors of ER stress or its signaling kinase PERK also suppressed RLDC-induced fibrotic changes and the expression of inflammatory cytokines. Interestingly, RLDC-induced PKCδ activation, which was blocked by ER stress or PERK inhibitors, suggesting PKCδ may act downstream of PERK. Indeed, suppression of PKCδ with a kinase-dead PKCδ (PKCδ-KD) or Pkcδ-shRNA attenuated RLDC-induced fibrotic and inflammatory changes. Moreover, the expression of active PKCδ-catalytic fragment (PKCδ-CF) diminished the beneficial effects of PERK inhibitor in RLDC-treated cells. Co-immunoprecipitation assay further suggested PERK binding to PKCδ.
These results indicate that ER stress contributes to chronic kidney pathologies following cisplatin chemotherapy via the PERK-PKCδ pathway.
顺铂是一种有效的化疗药物，但它可能会引起急性和慢性肾脏问题。顺铂化疗相关慢性肾脏病（CKD）的发病机制在很大程度上仍不清楚。
用重复小剂量顺铂（RLDC）处理小鼠和肾小管细胞，以诱导 CKD 及相关病理改变。用药理学抑制剂和基因操作确定内质网（ER）应激、PERK 和蛋白激酶 C-δ（PKCδ）的作用。
RLDC 在体内和体外模型中诱导肾小管细胞的 ER 应激。RLDC 后立即给予 ER 应激抑制剂可减轻小鼠的肾功能障碍、肾小管萎缩、肾纤维化和炎症。在培养的肾近端小管细胞中，ER 应激或其信号激酶 PERK 的抑制剂也抑制 RLDC 诱导的纤维化变化和炎性细胞因子的表达。有趣的是，RLDC 诱导的 PKCδ 激活被 ER 应激或 PERK 抑制剂阻断，表明 PKCδ 可能位于 PERK 下游。事实上，用激酶失活的 PKCδ（PKCδ-KD）或 Pkcδ-shRNA 抑制 PKCδ 可减弱 RLDC 诱导的纤维化和炎症变化。此外，活性 PKCδ-催化片段（PKCδ-CF）的表达减弱了 PERK 抑制剂在 RLDC 处理细胞中的有益作用。共免疫沉淀实验进一步表明 PERK 与 PKCδ 结合。
这些结果表明，内质网应激通过 PERK-PKCδ 通路导致顺铂化疗后慢性肾脏病变。
