This study, conducted by Dr. Haisheng Zhou from the Department of Biochemistry and Molecular Biology at Anhui Medical University, China, and Dr. Guoling Zhou from the Center for Computational Integrative Biology at Massachusetts General Hospital, USA, has made significant strides in understanding diabetic nephropathy (DN), a severe complication of diabetes.
Their research identified G protein-coupled receptor 107 (GPR107) as a crucial protein that plays a protective role in the kidneys of individuals with DN. The findings, recently published in Molecular Biomedicine, provide new insights into the mechanisms behind this debilitating disease and suggest GPR107 as a potential therapeutic target.
Diabetic nephropathy is one of the leading causes of kidney failure worldwide. A hallmark of DN is the thickening of the glomerular basement membrane (GBM), which occurs due to an abnormal buildup of COL4. The study reveals that GPR107 is essential for maintaining a proper balance of COL4 in podocytes, the filtering cells in the kidneys.
Researchers found that GPR107 acts as a key regulator of COL4 levels in the kidney. Reduced GPR107 function in diabetic kidneys leads to harmful accumulation of COL4, causing GBM thickening and subsequent kidney damage. The team discovered that GPR107 facilitates the internalization of angiotensin II receptor type 1 (AT1R) through clathrin-mediated endocytosis in podocytes.
However, in diabetic kidneys where GPR107 is deficient, this internalization process is impaired. This results in increased AT1R signaling, triggering a cascade that promotes COL4 production and inhibits its breakdown. Key findings from the study include:
- Significantly lower levels of GPR107 were found in kidney tissue from both human diabetic nephropathy patients and mice with streptozocin (STZ)-induced DN, a model of this condition.
- Mice lacking GPR107 developed more severe kidney damage after STZ-induced injury compared to controls.
- In laboratory experiments, exposure of podocytes to high glucose levels in the absence of GPR107 led to excessive accumulation of COL4.
These findings underscore the critical role that GPR107 plays not only in internalizing AT1R but also in regulating downstream signaling pathways involved in controlling COL4 production and degradation. This insight highlights the potential for GPR107 as a therapeutic target to address diabetic nephropathy.
The research team is now focusing on developing strategies aimed at restoring or enhancing GPR107 function within kidney cells, which could represent a novel approach to preventing or mitigating DN progression. These findings provide strong support for the development of targeted therapies specifically designed to correct GPR107 dysregulation in diabetic kidneys.
Future research will involve exploring potential drug candidates that can modulate GPR107 activity and investigating its role in other aspects of kidney health, potentially opening new avenues for treatment options tailored to this specific medical condition.
