Abstract: FR-PO0297
Mechanistic Role of GLP-1 Receptor Agonists in Suppressing Adenine-Induced Fibrotic Signaling Independent of Weight Loss
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 1
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Das, Falguni, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States
- Lee, Hak Joo, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States
- Kanduri, Swetha Rani, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States
- Sharma, Kumar, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States
Background
GLP-1 receptor agonists (GLP-1RAs) exhibit renoprotective effects in type 2 diabetes mellitus (T2DM); however, the underlying molecular mechanisms remain poorly defined. We previously demonstrated that elevated adenine contributes directly to kidney injury via glomerulosclerosis, tubular atrophy, and interstitial fibrosis. This study investigates whether GLP-1RA can mitigate adenine-induced renal fibrosis independently of adipocyte or insulin effects.
Methods
Human renal proximal tubular epithelial cells (HK-2) were employed for in vitro experiments. Techniques used included immunoblotting, immunoprecipitation, transfection assays, and measurement of hypertrophy.
Results
Treatment of HK-2 cells with 20 µM adenine induced inactivating phosphorylation of tuberin, a substrate of Akt, resulting in mTORC1 activation, as evidenced by increased phosphorylation of S6 kinase and 4EBP-1.Both rapamycin, an mTOR inhibitor, and a dominant negative (DN )-mTOR effectively suppressed adenine-induced phosphorylation of S6 kinase and 4EBP-1. GLP-1RA treatment attenuated adenine-induced Akt activation and reduced tuberin phosphorylation. Moreover, GLP-1RA significantly suppressed mTORC1 activation, which was induced by adenine. Adenine exposure also upregulated fibronectin and collagen I (α2) expression and promoted proximal tubular hypertrophy, hallmarks of kidney disease in T2DM. GLP-1RA inhibited adenine-induced expression of fibrotic proteins and hypertrophy. Further, to determine if GLP-1RA acts upstream of PI3K, we co-transfected cells with constitutively active (CA) forms of PI3K catalytic subunit (Myr-p110), Akt (Myr-Akt), and mTORC1 (CA-mTORC1) alongside adenine and GLP-1RA treatment. GLP-1RA significantly inhibited adenine induced expression of ECM proteins and hypertrophy, which was reversed by overexpression of CA-PI3K, CA-Akt and CA-mTORC1, demonstrating that GLP-1RA blocks PI3K-Akt-mTORC1-mediated ECM protein expression.
Conclusion
Our findings uncover a novel mechanism by which GLP-1RA attenuates adenine-induced signaling in HK-2 cells, reducing hypertrophy and ECM accumulation key features of diabetic kidney disease. These findings provide new insights into the molecular basis of GLP-1RA's renoprotective effects and may inform the development of novel therapeutic strategies for diabetic kidney disease, independent of weight loss.
Funding
- Veterans Affairs Support