This study, led by Dr. Haisheng Zhou from Anhui Medical University’s Department of Biochemistry and Molecular Biology in China, and Dr. Guoling Zhou from the Center for Computational Integrative Biology at Massachusetts General Hospital in the USA, has identified a crucial protein known as G protein-coupled receptor 107 (GPR107). This discovery offers significant insights into diabetic nephropathy (DN), which is a serious complication of diabetes.
The findings, recently published in Molecular Biomedicine, suggest that GPR107 plays a protective role in the kidneys of individuals with DN. DN is one of the leading causes of kidney failure worldwide and is characterized by thickening of the glomerular basement membrane (GBM) due to abnormal accumulation of COL4.
The research reveals that GPR107 is essential for maintaining proper COL4 balance within kidney filtering cells called podocytes. Researchers discovered that GPR107 acts as a key regulator of COL4 levels in the kidneys, finding that reduced GPR107 in diabetic kidneys contributes to harmful COL4 accumulation, resulting in GBM thickening and kidney damage.
Furthermore, they found that GPR107 facilitates the internalization of angiotensin II receptor type 1 (AT1R) in podocytes through clathrin-mediated endocytosis. In diabetic kidneys with reduced GPR107, this process is impaired, leading to increased AT1R signaling. This triggers a cascade that promotes COL4 production and inhibits its breakdown.
Key findings from the study include:
- Significantly Lower Levels of GPR107: The team observed lower levels of GPR107 in kidney tissue samples from both human DN patients and mice with streptozocin (STZ)-induced DN, a model used to simulate diabetic nephropathy.
- Severe Kidney Damage: Mice lacking GPR107 developed more severe kidney damage after being induced with STZ.
- GPR107 Deficiency in Podocytes: In laboratory studies, podocytes exposed to high glucose levels and deficient in GPR107 showed excessive COL4 accumulation.
- Regulation of Downstream Signaling Pathways: The study highlights that GPR107’s role extends beyond internalizing AT1R; it also regulates downstream signaling pathways controlling COL4 production and degradation.
These findings underscore the potential of GPR107 as a therapeutic target in diabetic nephropathy. Strategies to restore or enhance GPR107 function could offer a novel approach to preventing or mitigating the progression of this debilitating disease. The research provides strong support for developing targeted therapies that address GPR107 dysregulation in the diabetic kidney.
The research team is now focused on exploring potential drug candidates that can modulate GPR107 activity and further investigating its role in other aspects of kidney health.
