Interleukin 6 Mediated Activation of the Mineralocorticoid Receptor in the Aldosterone Sensitive Distal Nephron.
American journal of physiology. Cell physiology(2022)
Abstract
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 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 which 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 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 which was reversed with MR antagonist co-treatment, 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 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.
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Key words
cytokine,epithelial transport,hypertension,mineralocorticoid receptor,sodium
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