Abstract: TH-PO0282
Preventive RAAS Inhibition Is Associated with Marked Improvement in APOL1-Mediated Kidney Disease in APOL1 BAC Transgenic Mice
Session Information
- Glomerular Diseases: Cell Biology
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Sula Karreci, Esilida, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Foster, Anna, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Jacas, Sonako, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Huang, Huihui, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Friedman, David, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Pollak, Martin, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
Background
APOL1 high-risk variants are strongly associated with focal segmental glomerulosclerosis (FSGS) and progressive kidney disease, yet no preventive therapies exist for genetically at-risk individuals. The renin–angiotensin–aldosterone system (RAAS) contributes to podocyte injury and glomerular stress across proteinuric kidney diseases. In previous studies, we have shown that ACE inhibitor treatment significantly attenuated proteinuria and kidney injury in G1G1 APOL1 BAC transgenic mice, whereas a more modest effect was observed in G2G2 mice, even at higher doses. Whether early RAAS inhibition can further modify the trajectory of APOL1-mediated kidney injury prior to overt disease onset remains unknown.
Methods
We utilized a bacterial artificial chromosome (BAC) transgenic mouse model expressing APOL1 high-risk variants to evaluate the impact of RAAS inhibition on disease initiation and progression. APOL1 BAC transgenic mice expressing G1G1 or G2G2 variants (8–12 weeks of age, equal numbers of males and females) were randomized to receive an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) as pre-treatment (before disease induction) or no treatment. Outcomes included longitudinal urine albumin-to-creatinine ratio, serum creatinine, and histologic assessment of glomerulosclerosis and podocyte injury.
Results
Untreated APOL1 BAC transgenic mice developed progressive proteinuria and histologic features consistent with focal segmental glomerulosclerosis (FSGS). Preventive RAAS inhibition (ACEi or ARBs) was associated with marked improvement in proteinuria, preservation of podocyte architecture, reduced FSGS-like lesions, and better preservation of kidney function over time in both high-risk genotypes compared with untreated controls.
Conclusion
Preventive RAAS inhibition is associated with marked attenuation of proteinuria and reduced structural kidney injury in a BAC transgenic model of APOL1-mediated kidney disease. Our findings suggest that the protective effects previously observed with ACE inhibition are mediated primarily through angiotensin II type 1 receptor (AT1R) signaling. These findings support a potential disease-modifying role for early RAAS blockade and provide a strong preclinical rationale for translational studies in individuals at high genetic risk for APOL1-associated kidney disease.