Abstract: FR-PO939
The Role of SOAT1 in Renal Disease Associated with Alport Syndrome
Session Information
- Glomerular Diseases: Podocyte Biology - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Liu, Xiaochen, University of Miami Miller School of Medicine, Miami, Florida, United States
- Ducasa, Gloria Michelle, University of Miami Miller School of Medicine, Miami, Florida, United States
- Merscher, Sandra M., University of Miami, Miami, Florida, United States
- Fornoni, Alessia, University of Miami, Miami, Florida, United States
Background
Defective cholesterol metabolism is closely associated with the progression of renal disease in Alport syndrome(AS), an inherited disease associated with progressive kidney failure, hearing loss and eye abnormalities. We recently demonstrated that accumulation of cholesterol esters occurs in experimental models of AS. SOAT1 is an enzyme that converts free cholesterol to cholesteryl esters at the endoplasmic reticulum, and plays an important role in cellular cholesterol homeostasis. Recent studies indicate that inhibition of SOAT1 may have beneficial effects in Alzheimer’s disease and in cancer where SOAT1 inhibition reduced cancer proliferation and suppressed tumor growth. However, whether the accumulation of free or of esterified cholesterol contributes to progression of renal disease in AS remains unclear. With this study, we aimed at investigating the role of SOAT1 in the progression of renal disease in AS.
Methods
Normal human podocytes were treated with SOAT1 inhibitor (SI) or DMSO for 48h. Podocytes were stained with Bodipy and Cell Mask Blue. The Opera High Content screening system and Image Analysis software were used to quantify the density of lipid droplets. Cholesterol and triglyceride content was assessed using the Amplex Red Cholesterol kit and Triglyceride Colorimetric kit. Urinary albumin-to creatinine ratios were determined by mouse albumin ELISA and creatinine Companion kits.
Results
We observed a significant reduction of cholesterol esters in SI-treated human podocytes when compared to vehicle-treated podocytes in association with a decrease in lipid droplet density and triglyceride content. To assess the effect of SOAT1 deficiency in the kidney, the renal phenotype of Soat1 knockout (SKO) mice was investigated. SKO mice did not develop albuminuria or mesangial expansion at 10 months of age. Analysis of SOAT1 expression in kidney cortexes of AS mice demonstrated increased SOAT1 mRNA when compared to WT mice, while expression levels of several other genes important in cholesterol homeostasis remained unchanged.
Conclusion
Our data suggest that increased SOAT1 expression in the kidney cortex of AS mice contributes to progression of renal disease in AS. We conclude that preventing cholesterol ester accumulation in kidney cortex of AS mice by SOAT1 inhibition may represent a new therapeutic strategy to treat renal disease in AS patient.
Funding
- NIDDK Support