Abstract: SA-PO787
Uremia Modulates the Action of Simvastatin on the ABCA1 (ATP-Binding Cassette Transporter-1) in Endothelial Cells
Session Information
- CKD: Mechanisms - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- De melo, Silmara Fernandes, Universidade Federal de São Paulo, São Paulo, Brazil
- Nakamichi, Renata, Universidade Federal de São Paulo, São Paulo, Brazil
- Dalboni, Maria, Universidade Federal de São Paulo, São Paulo, Brazil
- Quinto, Beata M r, Universidade Federal de São Paulo, São Paulo, Brazil
- Batista, Marcelo Costa, Universidade Federal de São Paulo, São Paulo, Brazil
Group or Team Name
- UNIFESP
Background
Ligands of the retinoid X receptor (RXR) and liver X receptor (LXR) activate ABCA1 in endothelial cells at levels of both promoter activation and mRNA induction. ABCA-1 has a broad specificity in cholesterol efflux in endothelial cell and is highly modulated by statins. Chronic kidney disease (CKD) drives an epidemic cardiovascular burden due to neurohumoral dysfunction related with uremic state. We investigated the role of sinvastatin on ABCA1 modulation by LXR-β/RXR-α pathway in HUVEC cells exposed to uremic serum of patients under regular hemodialysis.
Methods
Previously characterized HUVEC cells were pre-treated with statin and stimulated with uremic serum for the same period. TNF-α and IL-10 levels were measured in cell supernatant. The expression of ABCA-1, LXR-β and RXR-α was analyzed by real-time PCR. Transfection of HUVEC cells was performed for analysis of ABCA-1 and promoter activation mediated by LxR-β and RxR-α, evaluation was carried out by flow cytometry and Western blot.
Results
In HUVEC cells, uremic state reduced the expression of LXR-β and RXR-α receptors without changing ABCA-1 expression. Simvastatin reversed the decrease of LXR-β and RXR-α expression observed in HUVEC cells incubated with uremic serum leading to a significant increase in ABCA-1 expression. The 3-HMCoA reductase inhibitor reversed the TNF-α increased secretion observed under uremic state without modifying IL-10. Sinvastatin-treated cells had a significant increase in transcription activation of LxR-β/RxR-α inducing ABCA-1 expression gene. Uremic state promoted a significant reduction in ABCA-1 transcription activation which was reversed by simvastatin.
Conclusion
We demonstrated that sinvastatin reduced inflammatory response of HUVEC cells exposed to uraemia by decreasing TNF-α secretion. We sugest that attenuation of inflammation observed by the 3-HMCoA reductase inhibitor is promoted through LxR-β/RxR-α pathway activation and consequent upregulation of ABCA-1 expression. Our study provides a potential role of statins on endothelial protection in CKD patients.
Funding
- Government Support - Non-U.S.