The Gastrin-releasing Peptide Receptor (GRPR), a Gαq -coupling neuropeptide receptor, belongs to the G protein-coupled receptors (GPCRs) family. It binds ligands like gastrin-releasing peptide (GRP) and is involved in various biological processes. GRP/GRPR signalling is associated with multiple pathophysiological pathways, including those related to inflammatory, cardiovascular, neurological diseases, and cancers [2].

Genetic deletion of GRPR in Grpr -/- and Grprflox/floxLysMCre mice alleviated ethanol-induced liver injury, with reduced steatosis, lower levels of liver function markers, decreased neutrophil influx, and reduced inflammatory cytokine expression, indicating its role in alcohol-associated liver injury [1]. In hyperuricemia-induced kidney fibrosis, GRPR knockout or conditional knockout in renal tubular epithelial cells of HN mice significantly alleviated renal function decline and fibrosis, suggesting GRPR enhances such injury via ABCG2 -dependent mechanisms [3]. Also, in acute kidney injury (AKI), genetic deletion of GRPR from tubular epithelial cells in GRPRFlox/Flox//KspCre mice protected against cisplatin-and ischemia-induced AKI, as GRPR interacted with Toll-like receptor 4 to activate STAT1, leading to TEC necroptosis and inflammation [4].

In conclusion, GRPR is involved in multiple biological processes and plays a significant role in diseases such as alcohol-associated liver injury, hyperuricemia-induced renal inflammation and fibrosis, and acute kidney injury. Gene knockout and conditional knockout mouse models have been crucial in revealing its pathogenic role in these disease conditions, providing potential therapeutic targets for treatment [1,3,4].

References:

1. Li, Haidi, Chen, Xin, Xu, Jiejie, Meng, Xiao-Ming, Li, Jun. 2023. GRP/GRPR enhances alcohol-associated liver injury through the IRF1-mediated Caspase-1 inflammasome and NOX2-dependent ROS pathway. In Hepatology (Baltimore, Md.), 79, 392-408. doi:10.1097/HEP.0000000000000531. https://pubmed.ncbi.nlm.nih.gov/37409771/

2. Sun, Hao-Lu, Ma, Qiu-Ying, Bian, He-Ge, Meng, Xiao-Ming, Jin, Juan. 2023. Novel insight on GRP/GRPR axis in diseases. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 161, 114497. doi:10.1016/j.biopha.2023.114497. https://pubmed.ncbi.nlm.nih.gov/36933382/

3. Sun, Hao-Lu, Bian, He-Ge, Liu, Xue-Mei, Meng, Xiao-Ming, Jin, Juan. 2023. GRP/GRPR signaling pathway aggravates hyperuricemia-induced renal inflammation and fibrosis via ABCG2-dependent mechanisms. In Biochemical pharmacology, 218, 115901. doi:10.1016/j.bcp.2023.115901. https://pubmed.ncbi.nlm.nih.gov/38084678/

4. Li, Chao, Ma, Qiu-Ying, Liu, Xue-Qi, Yao, Ri-Sheng, Meng, Xiao-Ming. 2023. Genetic and pharmacological inhibition of GRPR protects against acute kidney injury via attenuating renal inflammation and necroptosis. In Molecular therapy : the journal of the American Society of Gene Therapy, 31, 2734-2754. doi:10.1016/j.ymthe.2023.06.016. https://pubmed.ncbi.nlm.nih.gov/37415332/