Kidney Week

Abstract: FR-PO0187

Knocking Out Sphingosine 1-Phosphate Receptor 1 (S1PR1) Attenuates T Cell-Dependent Diabetic Kidney Disease

Session Information

• Diabetic Kidney Disease: Metabolic, Mitochondrial, and Inflammatory Mechanisms
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Cardiovascular-Kidney-Metabolic Health

• 601 Cardiovascular-Kidney-Metabolic Health: Basic

Authors

• Itani, Maha Mohammad, American University of Beirut Faculty of Medicine, Beirut, Beirut Governorate, Lebanon

Maha Mohammad Itani, PhD

• Sharaf AlDeen, Kawthar Hasan, American University of Beirut, Beirut, Beirut Governorate, Lebanon

Kawthar Hasan Sharaf AlDeen, MS

• Jaffa, Miran A., American University of Beirut, Beirut, Beirut Governorate, Lebanon

Miran A. Jaffa, PhD

• Ziyadeh, Fuad N., American University of Beirut Faculty of Medicine, Beirut, Beirut Governorate, Lebanon

Fuad N. Ziyadeh, MD, FASN

• Itani, Hana A., Regeneron Pharmaceuticals Inc, Tarrytown, New York, United States

Hana A. Itani, PhD, MBA, FASN

• Jaffa, Ayad A., American University of Beirut Faculty of Medicine, Beirut, Beirut Governorate, Lebanon

Ayad A. Jaffa, PhD

Background

Diabetic kidney disease (DKD) is driven by complex metabolic, hemodynamic, and inflammatory pathways. Sphingosine-1-phosphate receptor 1 (S1PR1) is a master regulator of T-lymphocyte trafficking and immune activation. We hypothesized that T-cell-specific S1PR1 signaling promotes Diabetic Kidney Disease (DKD) progression and that its targeted deletion confers renoprotection.

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. Over a 15-week period, we monitored metabolic parameters and albumin excretion rate (AER). Renal structural injury was quantified via mesangial expansion (PAS staining), while immune dynamics were assessed through CD4+ T-cell infiltration (flow cytometry) and inflammatory gene expression (qPCR).

Results

Hyperglycemia was similarly induced in both S1PR1^+/+ and S1PR1^−/− diabetic cohorts. Despite comparable hyperglycemia profiles, S1PR1^−/− mice exhibited a 46% reduction in AER (p<0.034) and significant attenuation of mesangial expansion compared to diabetic S1PR1^+/+ mice. This structural protection correlated with a dramatic reduction in immune recruitment: renal CD4+ T-cell infiltration was significantly lower in mice (17%) compared to littermates (28.6%, p<0.0002). Furthermore, T-cell-specific S1PR1 deletion suppressed the intrarenal expression of key profibrotic and inflammatory markers, including TGF-β1, TNFα-, and NGAL.

Conclusion

Targeted deletion of S1PR1 in T cells confers significant renoprotection by reducing albuminuria, structural injury, and renal inflammation independent of glycemic control. By specifically implicating T-cell trafficking, these findings identify a sophisticated, selective immunomodulatory axis in DKD. Given that S1P modulators are already clinically utilized in other inflammatory pathologies, this study provides preclinical validation of a pharmacologically tractable and clinically actionable target for the treatment of diabetic kidney disease.

Funding

• Other NIH Support