Discovery of a novel GRPR antagonist for protection against cisplatin-induced acute kidney injury

Abstract

The side effects of acute Kidney Injury (AKI) and nephrotoxicity limit the application of cisplatin in cancer treatment. Inflammation and oxidative stress paly important role in the pathogenesis of cisplatin-induced AKI. Gastrin-releasing peptide receptor (GRPR) plays an important role in inflammatory response. In this study, we designed 34 new Pd176252 analogs, most synthesized compounds could reduce cisplatin-induced HK2 cell death. Of these compounds, 9b had strong binding affinity with GRPR, and significantly increased HK2 cell viability. Compound 9b significantly downregulated the level of creatinine, blood urea nitrogen (BUN), and malondialdehyde (MDA), and recovered the glutathione (GSH) level in cisplatin-induced AKI model. It also decreased the level of kidney injury molecule-1(KIM-1) in vitro and vivo. In the further pathogenesis studies, 9b downregulated level of inflammatory factors (TNF-α, IL-1β, IL-6 and MCP-1), suppressed the nuclear factor-kappa B (NF-kB) phosphorylation, and decreased GRPR level. The results suggested that ameliorating cisplatin-induced AKI actions of 9b was involved in downregulation of TNF-α, IL-1β, IL-6, and MCP-1, inhibition of NF-kB activation, and reduction of GRPR and oxidative stress level.

Keywords: Acute kidney injury; Cisplatin; GRPR; Pd176252.