Restoration of E-cadherin by PPBICA protects against cisplatin-induced acute kidney injury by attenuating inflammation and programmed cell death

Abstract

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-κB 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-κB-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.

Blocking Connexin-43 mediated hemichannel activity protects against early tubular injury in experimental chronic kidney disease

“…E-cadherin, ZO-1, and Claudin-2 whilst upregulating those more commonly associated with a mesenchymal phenotype and increased fibrosis, e.g. α-SMA, Ncadherin, and Snail [32][33][34]. Initiation is associated with disassembly and breakdown of adherens junctions and tight junctions, culminating in loss of cell adhesion and increased paracellular permeability.…”

“…Loss of E-cadherin (ECAD) mediated cell-cell adhesion is pivotal in initiating a series of phenotypic and morphological events that precede tubulointerstitial fibrosis [27,32,33], with the disassembly of the adherens junction (AJ) and tight junction (TJ) complexes linked to loss of epithelial stability, inflammation, fibrosis and impaired renal function [34,35]. In the present study, we combine in vivo and in vitro models of CKD to investigate if targeting Cx43 expression and hemichannel activity through genetic and pharmacological blockade, could negate loss of markers linked with tubular injury, ultimately improving function through diminished hemichannel activity, restoration of E-cadherin mediated cell-cell adhesion and reduced paracellular permeability.…”

Tubular injury triggers podocyte dysfunction by β-catenin–driven release of MMP-7

“…The means by which a soluble protease reaches the glomerulus requires further study but could theoretically occur through several pathways, including diffusion from nearby tubules. Further, it is well known that tubular injury can lead to tubular apoptosis, loss of barrier integrity, and the potential backleak of substances through injured tubules, which could affect glomeruli (31)(32)(33)(34). Finally, it is possible that MMP-7 enters the systemic circulation.…”

2-Methylquinazoline derivative 23BB as a highly selective histone deacetylase 6 inhibitor alleviated cisplatin-induced acute kidney injury

“…Apoptotic pathways in the tubular epithelium could be induced by caspase cascade activation, mitochondrial injury, ER stress, etc. Apoptosis also promoted the loss of renal epithelial cells that characterized AKI [11,34,35]. Accumulating evidences demonstrated that the activation of caspase 3 was predominant which responsible for renal tubular cell apoptosis in cisplatin-induced AKI [13,36].…”