1001-OR: Targeted Deletion of Sphingosine 1-Phosphate Receptor 1 (S1PR1) in T Cells Confers Renoprotection in Diabetic Mice

Introduction and Objective: Diabetic kidney disease (DKD) arises from complex metabolic, hemodynamic, and inflammatory mechanisms. Sphingosine-1-phosphate receptor 1 (S1PR1) signaling regulates T-lymphocyte trafficking and immune activation; however, its role in DKD progression remains incompletely defined. This study investigated whether T-cell-specific S1PR1 signaling contributes to DKD development. Methods: Diabetes was induced in mice with T-cell-specific deletion of S1PR1 (S1PR1−/−) and wild-type littermates (S1PR1+/+) using daily streptozotocin injections (50 mg/kg) for 3-5 days. Metabolic parameters and albumin excretion rate (AER) were assessed over 15 weeks. Renal injury was evaluated by mesangial expansion, CD4+ T-cell infiltration, and inflammatory gene expression using PAS staining, flow cytometry, and PCR analyses. Results: Plasma glucose levels were similarly elevated in diabetic S1PR1+/+ and S1PR1−/− mice compared with controls. Despite comparable hyperglycemia, diabetic S1PR1−/− mice exhibited a significant reduction in AER (46%, p<0.034) and attenuated mesangial expansion relative to diabetic S1PR1+/+ mice. Diabetes markedly increased renal CD4+ T-cell infiltration in S1PR1+/+ mice (28.6%), which was significantly reduced in S1PR1−/− mice (17%, p<0.0002). T-cell-specific S1PR1 deletion was also associated with decreased renal expression of inflammatory and injury markers, including TGF-β, TNF-α, and NGAL. Conclusion: Targeted deletion of S1PR1 in T cells confers significant renoprotection in diabetic mice by reducing albuminuria, preserving renal structure, and limiting inflammatory responses. These findings identify T-cell S1PR1 signaling as a novel immunomodulatory contributor to DKD progression and a potential therapeutic target. Disclosure M. Itani: None. K.H. SharafAlDeen: None. M.A. Jaffa: None. F.N. Ziyadeh: None. H. Itani: None. A. Jaffa: None. Funding Medical Practice Plan/ University Research Board- AUB