2. Academic Validation
  3. G protein-coupled receptor 107 deficiency promotes development of diabetic nephropathy

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

  • Mol Biomed. 2025 Feb 11;6(1):10. doi: 10.1186/s43556-025-00250-1.
Deping Xu 1 2,  Ziwen Tong 1,  Ping Yang 1,  Qiong Chen 1,  Suhua Wang 1,  Wei Zhao 1,  Linzi Han 1,  Yu Yin 3,  Ruyue Xu 1,  Min Zhang 4,  Chunlin Cai 5,  Deguang Wang 6,  Dandan Zang 7,  Guoling Zhou 8,  Haisheng Zhou 9 10
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, China.
  • 2 The Clinical Laboratory, Hefei Affiliated Hospital to Anhui Medical University, the Second People's Hospital of Hefei, Hefei, China.
  • 3 Department of Pathology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 4 The Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 5 Department of Pathophysiology, Anhui Medical University, Hefei, China.
  • 6 Department of Nephrology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 7 Center for Scientific Research, Anhui Medical University, Hefei, China.
  • 8 Center for Computational Integrative Biology (CCIB), Massachusetts General Hospital (MGH), Harvard Medical Colleague, Boston, MA, USA. GZHOU@CCIB.MGH.HARVARD.EDU.
  • 9 Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, China. haishengs@ahmu.edu.cn.
  • 10 Center for Scientific Research, Anhui Medical University, Hefei, China. haishengs@ahmu.edu.cn.
PMID: 39932642 DOI: 10.1186/s43556-025-00250-1
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.

Keywords

Collagen type IV; Diabetic nephropathy; Endocytosis; GPR107; Podocytes.

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