Dysregulated Glomerular S1P Metabolism Contributes to Glomerular Injury

Background: Genetic defects in sphingosine-1-phosphate (S1P) lyase (SGPL1) are associated with steroid-resistant nephrotic syndrome (NS), suggesting a causative role of S1P and aberrant sphingolipid (SL) metabolism in glomerular injury. S1P is a sphingolipid which, in the absence of its carrier, Apolipoprotein M (APOM), causes pro-apoptotic signaling. We demonstrated that altered glomerular APOM and SL related gene expression in patients with glomerular disease correlates with poor renal outcome. Alport Syndrome (AS) is an inherited glomerular disease (GD), most frequently caused by Col4a3 gene mutations, where lipid accumulation is thought to play a role in its pathogenesis. This study aims at investigating the role of APOM deficiency and S1P signaling in renal injury using Alport Syndrome as a model of APOM deficient glomerular disease. Methods: Publicly available glomerular expression data of SL related genes in glomeruli of CKD patients and in wildtype (WT) and Col4a3 knockout (Col4a3 KO) mice were analyzed. The SL content in renal cortices of the mice was also assessed. Mice were treated with 0.1uM S1P and urine ACR and renal histology were analyzed. Immortalized murine control (IMWT) and Col4a3 KO (IMAL) podocytes, and APOM knockdown (siAPOM) or scramble control (SC) human podocytes were treated with S1P or an Sgpl1 inhibitor. SL related gene expression was analyzed by qRT-PCR and Western blot. Apoptosis was assessed. Results: Multiple SL related genes, including APOM, showed similar differential expression in glomeruli of patients with NS, in glomeruli of Col4a3 KO mice and in IMAS. Renal cortical S1P content was significantly increased Col4a3 KO and S1P treatment of Col4a3 KO mice, of IMAL and siAPOM podocytes, but not of controls, resulted in increased ACR and apoptosis, respectively. Conclusion: Our data suggest that aberrant SL metabolism may contribute to glomerular injury. The observation that Col4a3 KO, IMAL and siAPOM but not controls were susceptible to S1P-mediated injury suggests a role for APOM deficiency in this process. Targeting pathways involved in the APOM/S1P signaling axis may represent novel treatment options for patients with glomerular diseases. Funding: NIDDK Support