G protein-coupled receptor 107 deficiency promotes development of diabetic nephropathy.

IF 6.3 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Deping Xu, Ziwen Tong, Ping Yang, Qiong Chen, Suhua Wang, Wei Zhao, Linzi Han, Yu Yin, Ruyue Xu, Min Zhang, Chunlin Cai, Deguang Wang, Dandan Zang, Guoling Zhou, Haisheng Zhou
{"title":"G protein-coupled receptor 107 deficiency promotes development of diabetic nephropathy.","authors":"Deping Xu, Ziwen Tong, Ping Yang, Qiong Chen, Suhua Wang, Wei Zhao, Linzi Han, Yu Yin, Ruyue Xu, Min Zhang, Chunlin Cai, Deguang Wang, Dandan Zang, Guoling Zhou, Haisheng Zhou","doi":"10.1186/s43556-025-00250-1","DOIUrl":null,"url":null,"abstract":"<p><p>Diabetic nephropathy (DN) is characterized by glomerular basement membrane (GBM) thickening, primarily due to the abnormal accumulation of collagen type IV (COL4) in the extracellular matrix (ECM) of podocytes. Podocytes endocytosis is crucial for maintaining COL4 balance and GBM integrity. Previous studies have shown that G protein-coupled receptor 107 (GPR107) facilitates clathrin-dependent transferrin internalization and recycling in murine embryonic fibroblast cells. Therefore, the aim of the study is to investigate the role of GPR107 in regulating COL4 balance within the podocytes ECM and its potential as a therapeutic target for DN. Here, we found a significant decrease in GPR107 expression in renal tissues from DN patients and streptozocin (STZ)-induced DN mice. Furthermore, GPR107-deficient mice with STZ-induced DN exhibited more severe kidney damage, marked by increased GBM thickening and COL4 accumulation. In vitro, GPR107 deficiency under high-glucose conditions promoted COL4 accumulation in the ECM of podocytes due to increased COL4 production and decreased COL4 degradation. Mechanistically, we demonstrated that GPR107 contributes to angiotensin II receptor type 1 (AT1R) internalization through clathrin-mediated endocytosis (CME) in podocytes. Therefore, GPR107 deficiency impairs AT1R internalization, leading to increased membrane-bound AT1R. This, in turn, activates the AT1R/Ca<sup>2+</sup> signaling pathway to promote phosphorylation of cAMP-response element-binding protein (CREB), ultimately enhancing COL4 synthesis and inhibiting the expression of matrix metalloproteinase 2 (MMP-2). These findings shed light on new functions of GPR107 in DN and offer new insights into a therapeutic target for DN.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"10"},"PeriodicalIF":6.3000,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular biomedicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1186/s43556-025-00250-1","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Diabetic nephropathy (DN) is characterized by glomerular basement membrane (GBM) thickening, primarily due to the abnormal accumulation of collagen type IV (COL4) in the extracellular matrix (ECM) of podocytes. Podocytes endocytosis is crucial for maintaining COL4 balance and GBM integrity. Previous studies have shown that G protein-coupled receptor 107 (GPR107) facilitates clathrin-dependent transferrin internalization and recycling in murine embryonic fibroblast cells. Therefore, the aim of the study is to investigate the role of GPR107 in regulating COL4 balance within the podocytes ECM and its potential as a therapeutic target for DN. Here, we found a significant decrease in GPR107 expression in renal tissues from DN patients and streptozocin (STZ)-induced DN mice. Furthermore, GPR107-deficient mice with STZ-induced DN exhibited more severe kidney damage, marked by increased GBM thickening and COL4 accumulation. In vitro, GPR107 deficiency under high-glucose conditions promoted COL4 accumulation in the ECM of podocytes due to increased COL4 production and decreased COL4 degradation. Mechanistically, we demonstrated that GPR107 contributes to angiotensin II receptor type 1 (AT1R) internalization through clathrin-mediated endocytosis (CME) in podocytes. Therefore, GPR107 deficiency impairs AT1R internalization, leading to increased membrane-bound AT1R. This, in turn, activates the AT1R/Ca2+ signaling pathway to promote phosphorylation of cAMP-response element-binding protein (CREB), ultimately enhancing COL4 synthesis and inhibiting the expression of matrix metalloproteinase 2 (MMP-2). These findings shed light on new functions of GPR107 in DN and offer new insights into a therapeutic target for DN.

求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
6.30
自引率
0.00%
发文量
0
审稿时长
10 weeks
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信