Genetic and pharmacological inhibition of GRPR protects against acute kidney injury via attenuating renal inflammation and necroptosis

急性肾损伤 药理学 癌症研究 坏死性下垂 基因敲除 STAT1 化学 医学 细胞生物学 受体 基因 生物 内科学 细胞凋亡 程序性细胞死亡 生物化学
作者
Chao Li,Qiuying Ma,Xue-Qi Liu,Hai-Di Li,Mingjun Yu,Shuai-shuai Xie,Wen‐xian Ma,Ying Chen,Jianan Wang,Ruo-bing He,He-ge Bian,Yuan He,Liquan Gao,Shengsong Deng,Hongmei Zang,Qian Gong,Jiagen Wen,Mingming Liu,Chen Yang,Haiyong Chen,Sai Zhu,Hui‐Yao Lan,Juan Jin,Risheng Yao,Xiao‐Ming Meng
出处
期刊:Molecular Therapy [Elsevier]
卷期号:31 (9): 2734-2754 被引量:2
标识
DOI:10.1016/j.ymthe.2023.06.016
摘要

Gastrin-releasing peptide (GRP) binds to its receptor (GRP receptor [GRPR]) to regulate multiple biological processes, but the function of GRP/GRPR axis in acute kidney injury (AKI) remains unknown. In the present study, GRPR is highly expressed by tubular epithelial cells (TECs) in patients or mice with AKI, while histone deacetylase 8 may lead to the transcriptional activation of GRPR. Functionally, we uncovered that GRPR was pathogenic in AKI, as genetic deletion of GRPR was able to protect mice from cisplatin- and ischemia-induced AKI. This was further confirmed by specifically deleting the GRPR gene from TECs in GRPRFlox/Flox//KspCre mice. Mechanistically, we uncovered that GRPR was able to interact with Toll-like receptor 4 to activate STAT1 that bound the promoter of MLKL and CCL2 to induce TEC necroptosis, necroinflammation, and macrophages recruitment. This was further confirmed by overexpressing STAT1 to restore renal injury in GRPRFlox/Flox/KspCre mice. Concurrently, STAT1 induced GRP synthesis to enforce the GRP/GRPR/STAT1 positive feedback loop. Importantly, targeting GRPR by lentivirus-packaged small hairpin RNA or by treatment with a novel GRPR antagonist RH-1402 was able to inhibit cisplatin-induced AKI. In conclusion, GRPR is pathogenic in AKI and mediates AKI via the STAT1-dependent mechanism. Thus, targeting GRPR may be a novel therapeutic strategy for AKI.
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