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Interleukin-6 (IL-6) is thought to be a mediator of this inflammatory process. Interestingly, increased Na<jats:sup>+<\/jats:sup> reabsorption within the ASDN does not always correlate with increases in aldosterone (Aldo), the primary hormone that modulates Na<jats:sup>+<\/jats:sup> reabsorption via the mineralocorticoid receptor (MR). Thus, understanding how increased ASDN Na<jats:sup>+<\/jats:sup> 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<jats:sup>+<\/jats:sup> 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<jats:sup>+<\/jats:sup> current. ROS and IL-6 increased <jats:sup>22<\/jats:sup>Na<jats:sup>+<\/jats:sup> 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<jats:sup>+<\/jats:sup> reabsorption, providing evidence for an alternative mechanism for stimulating ASDN Na<jats:sup>+<\/jats:sup> uptake during conditions where Aldo-mediated MR stimulation may not occur. <\/jats:p>","DOI":"10.1152\/ajpcell.00272.2021","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T11:16:23Z","timestamp":1659352583000},"page":"C1512-C1523","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Interleukin 6 mediated activation of the mineralocorticoid receptor in the aldosterone-sensitive distal nephron"],"prefix":"10.1152","volume":"323","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0861-4245","authenticated-orcid":false,"given":"Brandi M.","family":"Wynne","sequence":"first","affiliation":[{"name":"Department of Medicine, Nephrology, Emory University, Atlanta, Georgia"},{"name":"Department of Internal Medicine, Nephrology & Hypertension, University of Utah, Salt Lake City, Utah"},{"name":"Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah"},{"name":"Immunology, Inflammation and Infectious Disease Initiative, University of Utah, Salt Lake City, Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trinity K.","family":"Samson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Nephrology, Emory University, Atlanta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hayley C.","family":"Moyer","sequence":"additional","affiliation":[{"name":"Department of Medicine, Nephrology, Emory University, Atlanta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrieke J.","family":"van Elst","sequence":"additional","affiliation":[{"name":"Department of Medicine, Nephrology, Emory University, Atlanta, Georgia"},{"name":"Department of Physiology, Radboud University Medical Center, Nijmegen, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Auriel S.","family":"Moseley","sequence":"additional","affiliation":[{"name":"Department of Medicine, Nephrology, Emory University, Atlanta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gillian","family":"Hecht","sequence":"additional","affiliation":[{"name":"Department of Medicine, Nephrology, Emory University, Atlanta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oishi","family":"Paul","sequence":"additional","affiliation":[{"name":"Department of Medicine, Nephrology, Emory University, Atlanta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Otor","family":"Al-Khalili","sequence":"additional","affiliation":[{"name":"Department of Medicine, Nephrology, Emory University, Atlanta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celso","family":"Gomez-Sanchez","sequence":"additional","affiliation":[{"name":"G.V. 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