Abstract
Renal lipid dysmetabolism is increasingly recognized as a key contributor to glomerular disease progression, including Alport Syndrome. We previously identified alterations in the apolipoprotein M (APOM), sphingosine-1-phosphate (S1P), and S1P receptor 4 (S1PR4) signaling axis in human glomerular disease. In this dissertation, we investigated whether this pathway is altered in Alport Syndrome and whether its modulation provides a therapeutic benefit. Glomeruli and podocytes from Col4a3-/- mice, a mouse model of Alport Syndrome exhibited reduced APOM and increased S1PR4 expression, mirroring the pattern observed in human disease. Treatment beginning at early disease stages with recombinant APOM or with CYM50358, a selective S1PR4 antagonist, prevented progression to renal failure and reduced neutral lipid accumulation in glomeruli and podocytes. S1PR4 antagonism enhanced autophagy and lysosomal clearance of lipid droplets, while APOM treatment increased cholesterol efflux, indicating that each treatment promotes distinct lipid clearance pathways. APOM knockdown or S1PR4 overexpression in podocytes were sufficient to induce cell death, although neither manipulation produced lipid droplet accumulation, suggesting that neutral lipid accumulation is an Alport Syndrome-specific phenotype not caused by these alterations alone. Together, these findings identify the APOM/S1PR4 axis as a therapeutically targetable pathway that modulates podocyte lipid handling and protects against renal injury in Alport Syndrome.