Restoration of E-cadherin by compound 8J protects against cisplatin-induced acute kidney injury by attenuating inflammation and programmed cell death / 中国药理学与毒理学杂志

ABSTRACT

OBJECTIVE E-cadherin is a major component of tubular adherent proteins which maintain intercellular contacts and cell polarity in epithelial tissue, it is involved in the pathological process of renal cell carcinoma and fibrotic diseases via epithelial- mesenchymal transition. Although we and others found that expression of E-cadherin was significantly down-regulated in kidney suffered acute kidney injury (AKI), its function in AKI was still unknown, which was explored in the current study. METHODS We disrupted E-cadherin or restored E-cadherin with compound 8J in cisplatin-stimulated tubular epithelial cell lines, the cell damage and inflammation were evaluated, additionally, the thera?peutic potential of E-cadherin restoration was also determined in vivo. RESULTS We found that cisplatin reduced E-cadherin expression both in mouse kidney and tubular epithelial cell lines (mTECs). Adminis?tration of compound 8J restored the level of E-cadherin, thereby increased cell viability while attenuating programmed cell death, which may be mediated by deactivation of RIPK/MLKL axis, reduced membrane translocation of phosphor-MLKL and decreased cleavage of caspase 3. Compound 8J also suppressed inflammatory response in cisplatin- treated mTECs, which was correlated with suppressed NF- κB phorsphorylation and promoter activity. In contrast, disruption of E-cadherin enhanced cell damage and inflammation. Treatment of compound 8J failed to further attenuate kidney damage in E- cadherin knockdown cells, indicating compound 8J protected against mTECs mainly through restoring E-cadherin. We also found that peritoneal injection of compound 8J protected against renal function and tubular damage by preventing NF-κB-driven renal inflammation and RIPK/MLKL-regulated programmed cell death, which was led by restoration of E-cadherin in cisplatin nephropathy. CONCLUSION More than a victim degraded after kidney injury, E-cadherin also has functional role in controlling tubule integrity, programmed cell death and renal inflammation. In this regard, restoration of E-cadherin by compound 8J should be considered as a novel therapeutic strategy for acute kidney injury.