Abstract: FR-PO0125
mTOR Signaling: A Key Player in X-Linked Alport Syndrome Disease Progression
Session Information
- Hereditary Glomerular and Tubulointerstitial Kidney Diseases
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)
Authors
- Willey, Courtney, The Jackson Laboratory, Bar Harbor, Maine, United States
- Sheehan, Susan Marie, The Jackson Laboratory, Bar Harbor, Maine, United States
- Reifsnyder, Peter C., The Jackson Laboratory, Bar Harbor, Maine, United States
- Spellacy, Samantha, The Jackson Laboratory, Bar Harbor, Maine, United States
- Korstanje, Ron, The Jackson Laboratory, Bar Harbor, Maine, United States
Background
Alport syndrome is a rare genetic condition that leads to progressive loss of kidney function and end-stage kidney disease. Although causal genes are well defined, patients show wide variation in disease severity and age of onset, suggesting the presence of modifier genes. Using Diversity Outbred mice with X-Linked Alport Syndrome (XLAS), we identified Dgke and Pik3r1 as potential modifier genes associated with the mammalian target of rapamycin (mTOR) signaling pathway.
Methods
To investigate this, we inhibited mTOR signaling in male Col4a5 knockout mice with XLAS, which exhibit a more severe XLAS phenotype. Treatment with the mTOR inhibitor rapamycin starting at 8-weeks of age extended lifespan by 44% compared to controls. Because rapamycin can have undesirable side effects in humans, we repeated the experiment using rapamycin and three alternative interventions (meclizine, alpelisib, and fisetin) starting at 4-weeks of age. These drugs inhibit mTOR signaling through distinct mechanisms and may provide safer therapeutic options.
Results
Glomerular filtration rate, a measure of kidney function, showed no significant treatment effects, while albumin-to-creatinine ratio, a measure of kidney damage, demonstrated that rapamycin, meclizine, and fisetin significantly reduced kidney damage.
Conclusion
Together, these findings show that targeting specific components of the mTOR pathway can reduce kidney damage in XLAS mice and highlight mTOR pathway modulation as a promising therapeutic strategy for Alport-related kidney disease.
Funding
- NIDDK Support