mTOR Signaling is a Key Modifier and Therapeutic Target in a Mouse Model of X-linked Alport Syndrome.

X-linked Alport syndrome (XLAS) is a hereditary kidney disease with substantial phenotypic variability despite well-defined causal mutations in type IV collagen. To identify modifier pathways influencing disease severity, we previously generated and analyzed a population of ~200 genetically diverse mice with XLAS and identified two candidate genes associated with albuminuria (Dgke and Pik3r1) both involved in the PI3K-AKT-mTOR pathway. To investigate the involvement of the PI3K-AKT-mTOR pathway in XLAS, we inhibited mTOR with rapamycin and found that treatment extended time to renal failure by 44%, whereas partial mTORC2 reduction via Rictor haploinsufficiency did not alter disease. A multi-drug intervention showed that rapamycin, meclizine, and fisetin significantly reduced albumin-to-creatinine ratio (ACR) without improving glomerular filtration rate (GFR), indicating protection from kidney injury rather than restoration of filtration. Together, these findings highlight mTORC1 signaling as a key modifier of XLAS.