Abstract: SA-PO1177
IL-6 Mediated Activation of the Mineralocorticoid Receptor via Rac1
Session Information
- NIDDK KUH Summer Undergraduate Research Program Posters
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Author
Group or Team Name
- Oishi Paul. Emory University, Atlanta, GA.
Background
Hypertension (HTN) is characterized by excessive sodium (Na+) reabsorption and increased cytokine production, including interleukin 6 (IL-6). Aldosterone (Aldo) is the primary ligand for the mineralocorticoid receptor (MR) and studies suggest MR inhibition lowers blood pressure. However, Aldo levels are not always increased in HTN, suggesting alternate MR activation. Data from our laboratory have shown that IL-6 can activate the MR in vitro, and that Rac inhibition reduces mineralocorticoid response element (MRE) transcription. We hypothesize that IL-6 activates the MR via Rac1 in the late distal convoluted tubule (DCT), increasing activity of epithelial sodium channel (ENaC), a primary Na+ transporter in the late DCT (DCT2).
Methods
Using a voltohmmeter, we measured transepithelial resistance and voltage to calculate current in our cell culture model for DCT2 (mDCT15 cells). Cells were transfected with Rac1 expression vectors and treated (IL-6 [100ng/mL]).
Results
While IL-6 increased ENaC activity, Rac1 knockdown inhibited IL-6 induced ENaC (-1.16-fold change/baseline) activity. Since we observed that IL-6 induces nuclear MR translocation, we investigated whether Rac1 affects IL-6 mediated MR translocation. We cotransfected MR-eGFP tagged constructs and Rac1 expression vectors into mDCT15 cells. Cells were treated with IL-6 and visualized with confocal microscopy. Following IL-6 treatment, MR nuclear translocation was observed; however, with Rac1 knockdown, decreased MR translocation was observed.
Conclusion
We are the first to demonstrate cytokine-mediated ENaC activation in the DCT2. Additionally, these data suggest that Rac1 is crucial for IL-6 mediated ENaC activation and MR translocation, providing an alternate mechanism for increased ENaC Na+ transport during HTN.