Targeting Sphingosine-1-Phosphate Receptor 4 in a Mouse Model of Alport Syndrome
- Glomerular Diseases: From Inflammation to Fibrosis - III
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: From Inflammation to Fibrosis
- Tolerico, Matthew, University of Miami School of Medicine, Miami, Florida, United States
- Molina David, Judith T., University of Miami School of Medicine, Miami, Florida, United States
- Merscher, Sandra M., University of Miami School of Medicine, Miami, Florida, United States
- Fornoni, Alessia, University of Miami School of Medicine, Miami, Florida, United States
Alport syndome is a genetic condition in which the ability to produce the heterotrimer collagen 4a345 is disrupted. Alport syndrome results in glomerular disease and eventually renal failure. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that exerts its effects by interacting with one of its five receptors (S1PR1-5). S1P signaling has a wide range of effects depending on the receptor and the cell type. S1P siganling plays a large role in the immune system as lymphocyte migration is dependent on it. However the role of S1P siganling in podocytes and the kidney is largely unknown.
S1P was measured through liquid-chromatography mass spectrometry. Col4a3 -/- mice were treated with either vehicle or 25mg/kg CYM50358 (S1PR4 antagonist) every other day starting at 4 weeks of age until sacrifice at 8 weeks of age. Albumin to creatinine ratio was determined through ELISA. Mesangial expansion was determined by PAS staining. Lipid accumulation was determined by oil red o staining. Fibrosis was determined by picro-sirius red staining.
Col4a3 -/- mice have elevated S1P in the kidneys compared to control mice. We see higher kidney cortex expression of S1PR4 in Col4a3 -/- mice compared to control mice. We see that treatment with a S1PR4 antagonist is sufficent to lower proteinuria, lipid accumulation in the kidney, mesangial expansion and fibrosis.
Our results suggest that S1P may drive progression of renal failure in alport syndrome. We see that reducing S1PR4 signaling through pharmacological treatment is beneficial to renal outcomes in col4a3 -/- mice .Targeting other S1PR may be beneficial as well for slowing the progression of renal failure.
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