Alpha-NETA, as a CMKLR1 Small Molecule Antagonist, Protects against Renal Ischemia Reperfusion Injury in Mice

Abstract

Background: Ischemia-reperfusion (IR) injury is one of major causes of acute kidney injury (AKI). Chemerin chemokine-like receptor 1 (CMKLR1) has been reported to involved in the progression of IR injury. Here, we investigated the protective role of CMKLR1 antagonist, α-NETA, in IR mouse model, and dissected the underlying regulatory mechanism. Methods: IR injury mouse model was established to evaluate the protective effects of α-NETA on IR injury. Kidney injury associated parameters and functions were examined to evaluate the renal function of Sham, IR, and IR+ α-NETA mice. Renal morphological changes and apoptosis were determined by PAS and TUNEL staining in IR and α-NETA treated mice. ELISA, RT-qPCR, and western blot were performed to examine the inflammatory responses and expression of CMKLR1. Results: α-NETA administration attenuated IR-induced renal tubular injury and epithelial cell apoptosis in IR injury mice. Kidney injury related cystatin C, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and renal morphology were significantly improved. Mechanistically, α-NETA suppressed the inflammatory responses through inhibiting the expression of CMKLR1, and then protected the IR-induced renal damage and restored the renal function. Conclusion: CMKLR1 plays important role in renal ischemia-reperfusion injury, targeting CMKLR1 by using the small molecule inhibitor α-NETA is a potential treatment strategy for AKI.

Discovery of 3-Phenyl Indazole-Based Novel Chemokine-like Receptor 1 Antagonists for the Treatment of Psoriasis

“…Current CMKLR1 ligands, including agonists and antagonists, are presented in Figure . Among them, 2-(α-naphthoyl)­ethyltrimethylammonium iodide ( 1 , α-NETA), previously known as a choline acetyltransferase inhibitor, reportedly exerts a CMKLR1 antagonistic effect that functionally delays experimental autoimmune encephalomyelitis onset in C57BL/6 mice and elicits a protective effect in an ischemia-reperfusion mouse model. , Moreover, the therapeutic effect of pyrrolidinone carboxamide derivatives ( 2 )a potent CMKLR1 antagonist discovered by ChemoCentryxhas been investigated in the context of insulin signaling and esophageal cancer. , Recently, a 2-aminobenzoxazole derivative ( 3 ) was reported with potent CMKLR1 antagonistic activity and oral pharmacokinetic properties. , Additionally, Resolvin E1 ( 4 ) is an endogenous lipid mediator that exerts potent CMKLR1 agonistic activity and induces macrophage phagocytosis …”