GRP/GRPR signaling pathway aggravates hyperuricemia-induced renal inflammation and fibrosis via ABCG2-dependent mechanisms.
GRP/GRPR signaling pathway aggravates hyperuricemia-induced renal inflammation and fibrosis via ABCG2-dependent mechanisms.
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GRP/GRPR信号通路通过ABCG 2依赖性机制加重高尿酸血症诱导的肾脏炎症和纤维化
DOI：
10.1016/j.bcp.2023.115901
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发表时间：
2023-10
影响因子：
5.8
通讯作者：
Hao-lu Sun;He-ge Bian;Xue-mei Liu;Heng Zhang;Jie Ying;Hang Yang;Tong Zu;Guo-qiang Cui;Yan-fei Liao;Ma-fei Xu;Xiao-ming Meng;Juan Jin
中科院分区：
文献类型：
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作者：
Hao-lu Sun;He-ge Bian;Xue-mei Liu;Heng Zhang;Jie Ying;Hang Yang;Tong Zu;Guo-qiang Cui;Yan-fei Liao;Ma-fei Xu;Xiao-ming Meng;Juan Jin
The gastrin-releasing peptide receptor (GRPR) binds to ligands such as gastrin-releasing peptide (GRP) and plays a variety of biological roles. In this study, we investigated the therapeutic effect of a novel gastrin-releasing peptide receptor antagonist RH-1402 in hyperuricemia-induced kidney fibrosis and its underlying mechanisms. We conducted enzyme linked immunosorbent assay (ELISA) and immunohistochemical analyses and found that proGRP and GRPR expression levels were significantly increased in patients with hyperuricemic nephropathy (HN) and HN mice. GRPR knockdown significantly attenuated inflammatory and fibrotic responses in adenosine-treated human proximal tubule epithelial cells. GRPR knockout or GRPR conditional knockout in renal tubular epithelial cells significantly alleviated the decline in renal function and fibrosis in HN micein vivo. RNA-seq and String database analysis revealed that GRP/GRPR promoted HN by suppressing the ABCG2/PDZK1 and increasing TGF-β/Smad3 levels by activating the NF-κB pathway. Overexpression of GRPR increased TGF-β/Smad3 levels, where as it reduced ABCG2/PDZK1 levels in adenosine-treated HK2 cells, which was reversed by the NF-κB inhibitor. Furthermore, we evaluated the therapeutic effects of the novel GRPR inhibitor RH-1402 on hyperuricaemia-induced renal injury and evaluated the inflammatory and fibrosis responsesin vivoandin vitro. Pre-treatment with RH-1402 attenuated hyperuricaemia-induced renal injury, restored renal function, and suppressed renal inflammation and fibrosis. Taken together, GRPR enhances hyperuricaemia-induced tubular injury, inflammation, and renal fibrosis via ABCG2-dependent mechanisms and may serve as a promising therapeutic target for HN treatment.
