| Autor: |
Wynne BM; Department of Medicine, Nephrology, Emory University, Atlanta, Georgia.; Department of Internal Medicine, Nephrology & Hypertension, University of Utah, Salt Lake City, Utah.; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah.; Immunology, Inflammation and Infectious Disease Initiative, University of Utah, Salt Lake City, Utah., Samson TK; Department of Medicine, Nephrology, Emory University, Atlanta, Georgia., Moyer HC; Department of Medicine, Nephrology, Emory University, Atlanta, Georgia., van Elst HJ; Department of Medicine, Nephrology, Emory University, Atlanta, Georgia.; Department of Physiology, Radboud University Medical Center, Nijmegen, Netherlands., Moseley AS; Department of Medicine, Nephrology, Emory University, Atlanta, Georgia., Hecht G; Department of Medicine, Nephrology, Emory University, Atlanta, Georgia., Paul O; Department of Medicine, Nephrology, Emory University, Atlanta, Georgia., Al-Khalili O; Department of Medicine, Nephrology, Emory University, Atlanta, Georgia., Gomez-Sanchez C; G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi.; Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Mississippi., Ko B; Department of Medicine, Nephrology, University of Chicago, Chicago, Illinois., Eaton DC; Department of Medicine, Nephrology, Emory University, Atlanta, Georgia., Hoover RS; Department of Medicine, Nephrology, Emory University, Atlanta, Georgia.; Research Service, Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.; Section of Nephrology and Hypertension, Deming Department of Medicine, Tulane University, New Orleans, Louisiana. |
| Abstrakt: |
Hypertension is characterized by increased sodium (Na + ) reabsorption along the aldosterone-sensitive distal nephron (ASDN) as well as chronic systemic inflammation. Interleukin-6 (IL-6) is thought to be a mediator of this inflammatory process. Interestingly, increased Na + reabsorption within the ASDN does not always correlate with increases in aldosterone (Aldo), the primary hormone that modulates Na + reabsorption via the mineralocorticoid receptor (MR). Thus, understanding how increased ASDN Na + reabsorption may occur independent of Aldo stimulation is critical. Here, we show that IL-6 can activate the MR by activating Rac1 and stimulating the generation of reactive oxygen species (ROS) with a consequent increase in thiazide-sensitive Na + uptake. Using an in vitro model of the distal convoluted tubule (DCT2), mDCT15 cells, we observed nuclear translocation of eGFP-tagged MR after IL-6 treatment. To confirm the activation of downstream transcription factors, mDCT15 cells were transfected with mineralocorticoid response element (MRE)-luciferase reporter constructs; then treated with vehicle, Aldo, or IL-6. Aldosterone or IL-6 treatment increased luciferase activity that was reversed with MR antagonist cotreatment, but IL-6 treatment was reversed by Rac1 inhibition or ROS reduction. In both mDCT15 and mpkCCD cells, IL-6 increased amiloride-sensitive transepithelial Na + current. ROS and IL-6 increased 22 Na + uptake via the thiazide-sensitive sodium chloride cotransporter (NCC). These results are the first to demonstrate that IL-6 can activate the MR resulting in MRE activation and that IL-6 increases NCC-mediated Na + reabsorption, providing evidence for an alternative mechanism for stimulating ASDN Na + uptake during conditions where Aldo-mediated MR stimulation may not occur. |
