Restoration of E-cadherin by PPBICA protects against cisplatin-induced acute kidney injury by attenuating inflammation and programmed cell death
Restoration of E-cadherin by PPBICA protects against cisplatin-induced acute kidney injury by attenuating inflammation and programmed cell death
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PPBICA 恢复 E-钙粘蛋白可通过减轻炎症和程序性细胞死亡来防止顺铂诱导的急性肾损伤。
DOI：
10.1038/s41374-018-0052-5
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发表时间：
2018-07-01
影响因子：
5
通讯作者：
Meng, Xiao-Ming
中科院分区：
文献类型：
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作者：
Gao, Li;Liu, Ming-Ming;Meng, Xiao-Ming
e -钙粘蛋白是上皮组织中维持细胞间接触和细胞极性的小管粘附蛋白的主要成分。它通过上皮-间质转化参与肾细胞癌和纤维化疾病的病理过程。虽然研究表明e -钙粘蛋白在急性肾损伤（AKI）中显著下调，但其在AKI中的功能尚不清楚。在这里，我们评估了顺铂刺激的小管上皮细胞系在破坏e -钙粘蛋白并用PPBICA（一种通过高通量筛选鉴定的小分子）恢复后的细胞损伤和炎症。我们还确定了在体内恢复e -钙粘蛋白的治疗潜力。结果显示，顺铂降低了E-cadherin在小鼠肾和近端小管上皮细胞系（mTECs）中的表达。PPBICA恢复e -钙粘蛋白水平，从而增加细胞活力，同时减轻程序性细胞死亡。这可能是通过RIPK1/RIPK3轴失活和caspase3切割减少介导的。此外，PPBICA抑制顺铂治疗mtec的炎症反应，这与抑制NF-kappa B磷酸化和启动子活性相关。相反，e -钙粘蛋白的破坏促进了细胞损伤和炎症。PPBICA不能进一步减轻E-cadherin敲低细胞的肾损伤，表明PPBICA通过E-cadherin修复来保护mtec。我们还发现腹腔注射PPBICA小鼠通过抑制nf - κ b驱动的肾脏炎症和ripk调控的程序性细胞死亡，防止肾功能丧失和小管损伤。这是由e -钙粘蛋白在顺铂肾病中的恢复所驱动的。此外，PPBICA在已建立的AKI模型中减轻了顺铂引起的肾损害，表明其治疗AKI的治疗潜力。综上所述，e -钙粘蛋白在小管完整性、程序性细胞死亡和肾脏炎症中发挥功能作用。我们的研究结果强调了e -钙粘蛋白修复作为AKI新治疗策略的潜力。
E-cadherin is a major component of tubular adherent proteins that maintain intercellular contacts and cell polarity in epithelial tissue. It is involved in pathological processes of renal cell carcinoma and fibrotic diseases via epithelial-mesenchymal transition. Although studies have shown E-cadherin is significantly downregulated in acute kidney injury (AKI), its function in AKI is unknown. Here, we evaluated cell damage and inflammation in cisplatin-stimulated tubular epithelial cell lines after disrupting E-cadherin and restoring it with PPBICA, a small molecule identified by high-throughput screening. We also determined the therapeutic potential of restoring E-cadherin in vivo. Results show cisplatin reduced E-cadherin expression both in mouse kidney and proximal tubular epithelial cell lines (mTECs). PPBICA restored E-cadherin levels, which increased cell viability while attenuating programmed cell death. This may be mediated via deactivation of the RIPK1/RIPK3 axis and decreased caspase3 cleavage. In addition, PPBICA suppressed inflammatory response in cisplatin-treated mTECs, which correlated with suppressed NF-kappa B phosphorylation and promoter activity. In contrast, disruption of E-cadherin promoted cell damage and inflammation. PPBICA failed to further attenuate kidney damage in E-cadherin knockdown cells, indicating that PPBICA protects against mTECs through E-cadherin restoration. We also found that peritoneal injection of PPBICA in mice prevented loss of renal function and tubular damage by suppressing NF-kappa B-driven renal inflammation and RIPK-regulated programmed cell death. This was driven by restoration of E-cadherin in cisplatin nephropathy. Additionally, PPBICA attenuated cisplatin-induced kidney damage in an established AKI model, indicating its therapeutic potential in the treatment of AKI. In conclusion, E-cadherin plays functional roles in tubule integrity, programmed cell death, and renal inflammation. Our results underscore the potential of E-cadherin restoration as a novel therapeutic strategy for AKI.