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Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
99
GLP1R Gene Expression and Kidney Disease Progression.
Jefferson L Triozzi1, Zhihong Yu2, Ayush Giri3,4
1Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
JAMA Network Open
|October 25, 2024
Summary
Higher genetic expression of the glucagon-like peptide 1 receptor (GLP-1R) was linked to a reduced risk of kidney disease progression. This suggests GLP-1 receptor agonists may offer kidney protection beyond weight and glucose control.
Area of Science:
- Pharmacology and Nephrology
- Genetics and Precision Medicine
Background:
- Glucagon-like peptide 1 receptor agonists (GLP-1RAs) show potential for kidney protection.
- These benefits may extend beyond their established effects on weight and glycemic control.
Purpose of the Study:
- To investigate the association between genetically proxied GLP-1RAs and the progression of kidney disease.
- To explore potential nephroprotective mechanisms independent of metabolic factors.
Main Methods:
- A genetic association study using a national retrospective cohort from the US Department of Veterans Affairs Million Veteran Program (n=353,153).
- Calculated a genetic risk score for systemic GLP1R gene expression based on genetic variants.
- Assessed the primary composite outcome of incident end-stage kidney disease or a 40% decline in estimated glomerular filtration rate using Cox proportional hazards regression.
Main Results:
- Higher genetic GLP1R gene expression was associated with a lower risk of kidney disease progression (adjusted HR, 0.96; 95% CI, 0.92-1.00; P=.04).
- This association remained consistent in sensitivity analyses stratified by diabetes or obesity status.
- Approximately 4.6% of the cohort experienced kidney disease progression during a median follow-up of 5.1 years.
Conclusions:
- Increased GLP1R gene expression is linked to a modest reduction in kidney disease progression risk.
- Findings support pleiotropic nephroprotective effects of GLP-1RAs, independent of weight and glycemic control.
- Highlights the potential for genetic insights into drug mechanisms and therapeutic benefits.
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