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Utah's Foremost Platform for Undergraduate Research Presentation
2021 Abstracts

Interleukin-6 mediated regulation of ENaC via Time-Dependent MAPK Family Activation

Presenter: Harini Srinivasan, College of Science, Chemistry
Authors: Harini Srinivasan, Auriel S Mosely, Chang Song, Malu Tansey, Masaaki Yoshigi, Douglas C Eaton, Brandi M. Wynne
Faculty Advisor: Brandi Wynne, School of Medicine, Department of Internal Medicine
Institution: University of Utah

Hypertension is an inflammatory disease characterized by excessive sodium reabsorption by cells in the aldosterone-sensitive distal nephron, resulting in decreased water excretion and a systemic increase in blood pressure. Identification of new therapies is important, since anti-hypertensive drugs are often unsuccessful in regulating blood pressure. Interleukin-6 (IL6) levels are increased in plasma from hypertensive individuals. Our previous data suggests that IL6 can activate the mineralocorticoid receptor (MR) in vitro and in vivo, and increase blood pressure. However, the exact intracellular signaling pathways are unknown. RNA sequencing was utilized to uncover novel targets. These studies used the mDCT15 cell model for the DCT2; cells were treated with IL6 (100ng/mL, 24 hours) or vehicle (n=4, each), then total RNA isolated. Data from Illumina-sequenced transcriptome underwent comparative analysis to identify differentially expressed transcripts between vehicle and IL6 treated cells. These experiments revealed a pathway for the family of mitogen-activated protein kinases (MAPKs). We observed reductions in modulators of the JNK pathway, Map3k11 (padj, 0.01) and Mapk8ip3 (padj, 0.02) expression following IL6 treatment. We hypothesized that MAPK pathways are a downstream regulator of IL6. Using total protein from IL6 treated cells (30min), we observed an increase in pERK1/2 expression, with no changes in total ERK1/2 levels. To explore the role for ERK1/2 in ENaC activation, we measured transepithelial voltage and resistance using a voltohmmeter, and calculated current in mDCT15 cells (n=3/group) following IL6 treatment (1hr) and with an ERK1/2 inhibitor. IL6 increased amiloride-sensitive current, which was reduced with ERK1/2 inhibition. These data suggest an increase in pERK1/2 activation, followed with an increase in ENaC activation. We observed inhibition of the JNK-pathway members with 24hr IL6 stimulation, suggesting a negative-feedback regulation. These data support a time-sensitive role for IL6-mediated ENaC activation via MAPKs in the DCT and represent novel targets for alternate IL6-mediated MR activation.