Abstract: TH-OR072

Interleukin 6 Regulates the Epithelial Sodium Channel

Session Information

Category: Fluid, Electrolytes, and Acid-Base

  • 703 Na+, K+, Cl- Basic

Authors

  • Wynne, Brandi M., Emory University, Atlanta, Georgia, United States
  • Yue, Qiang, Emory University, Atlanta, Georgia, United States
  • Hecht, Gillian Grace, Emory University, Atlanta, Georgia, United States
  • van Elst, Henrieke Jacobien, Emory University, Atlanta, Georgia, United States
  • Moyer, Hayley C, Emory University, Atlanta, Georgia, United States
  • Eaton, Douglas C., Emory University, Atlanta, Georgia, United States
  • Hoover, Robert S., Emory University, Atlanta, Georgia, United States
Background

Hypertension is characterized by increased sodium (Na+) reabsorption along the aldosterone-sensitive distal nephron (ASDN), as well as a chronic systemic inflammation. Interleukin-6 (IL-6) is a mediator of this inflammatory process. We have previously demonstrated that IL-6 activates the mineralocorticoid receptor (MR), and increases sodium chloride cotransporter expression and activity. We hypothesized that IL-6 will increase ENaC activity and/or expression.

Methods

We used mpkCCD cells to determine amiloride-sensitive transepithelial voltage and resistance (EVOM) with IL-6 (100ng/mL, 18hrs). C57Bl6 (Wt) mice were perfused with IL-6 (16ng/min, intrarenal, 3d) or vehicle, and/or treated with spironolactone. Kidney cortex homogenates were used to determine ENaC (α, γ) expression. SGK1 immunofluorescence was determined in tissue slices. ENaC channel density (N) and activity (NPo) was obtained using split open tubules (cortical collecting duct, CCD) from IL-6 KO and Wt mice. Data are expressed as mean±SEM.

Results

Using EVOM, IL-6-mediated amiloride-sensitive current (7.4±0.7 vs. 6.2±0.7μAmp/cm2, n=6, p<0.0001) was increased. IL-6 perfusion increased ENaCα (≈1.49, n=3, p<0.05) and γ (≈3.14, n=8, p<0.05) protein expression, as compared to vehicle. SGK1 pixel intensity (PI) was increased following IL-6 perfusion (306±4.7 vs. 263±4.4PI, n=6, p<0.0001); spironolactone reduced this response (224.3±4.5PI vs. vehicle, n=6, p<0.0001). Baseline ENaC activity (NPo) was less than half in split open tubules from IL-6 KO mice, as compared to Wt (0.337±0.01 vs. 0.151±0.04, n=3, p<0.001).

Conclusion

Here, we show that IL-6 infusion increases ENaCα and γ protein expression, as well as SGK1 levels in an MR-dependent manner. Amiloride-sensitive current was also increased, corroborating the increased ENaC expression found following IL-6 perfusion. With whole animal IL-6 depletion, there was a significant reduction in ENaC activity. Together, our data suggest that a basal level of IL-6 is necessary to for adequate ENaC activity and that increased IL-6 levels may contribute to increased ENaC protein expression. Our data reveal a possible role for IL-6 mediated increases in ENaC expression and/or activity, which is especially important during hypertension.

Funding

  • NIDDK Support