IL‐6 Activates the Mineralocorticoid Receptor via the JAK2/STAT3 Pathway
Authors: Moyer Hayley Catherine , Krishnamurthy Ashwini , Mallick Rickta , Hoover Robert S. , Wynne Brandi Michele 
Published: June 2021

Hypertension is an inflammatory disease that is a leading cause of death and disability worldwide and is characterized by increased sodium (Na+) reabsorption. The beneficial effect of mineralocorticoid receptor (MR) antagonists in reducing blood pressure suggests a role for the MR in hypertension. Interestingly, the classical MR ligand, aldosterone (Aldo) is not always increased during hypertension. However, the pro‐inflammatory cytokine interleukin 6 (IL‐6) is elevated in the serum of hypertensive individuals. Previously we have shown that IL‐6 increases MR‐dependent Na+ uptake in vitro, and increases expression of the (Na+) chloride cotransporter (NCC) in vivo. IL‐6 signals through the IL‐6 receptor a (IL‐6Ra) and the small signaling molecule, gp130, activating multiple intracellular signaling pathways including the Janus Kinase (JAK)/Signal Transducer and Activation of Transcription (STAT) signaling pathway. There are multiple isoforms of each of these kinases which have been implicated in other IL‐6‐mediated inflammatory responses in the kidney. However, no studies have investigated how IL‐6 increases NCC‐mediated Na+ reabsorption, or the specific JAK/STAT pathway combination that may mediate this process. We hypothesize that the JAK2/STAT3 signaling pathway is involved in MR‐mediated activation of NCC.

We used an in vitro model of the late distal convoluted tubule (DCT2), mDCT15 cells. Cells were grown to confluence (60%), and then treated with IL‐6 (100 ng/mL, 24 hrs). Cells were stained for phosphor‐JAK2 and ‐STAT3 levels. We observed a significant increase in activation levels of this pathway. Phospho‐JAK2 levels were more than doubled (211%) following IL‐6 treatment, suggesting strong activation of the JAK2/STAT3 pathway following IL‐6 in distal nephron epithelial cells.

To demonstrate IL‐6‐mediated MR activation via the JAK2/STAT3 pathway, mDCT15 cells were transfected with mineralocorticoid response element (MRE)‐luciferase reporter constructs (5 mg), and treated with: vehicle, Aldo (100nM), IL‐6 (100 ng/mL) and/or the MR antagonist (spironolactone, 10 nM), the gp130 inhibitor (SC144, 2μM) and the STAT3 inhibitor (NSC74859, 100 μM) or the JAK1/2 inhibitor (Ruxolitinib, 250 nM). Luciferase assays were performed on whole cell lysates (48 hrs). We found that IL‐6 increased MRE activity (36%) over vehicle. When cells were co‐incubated with inhibitors for gp130 or STAT3, we saw a decrease in MRE activity to levels lower than vehicle. We did not observe a decrease in MRE activity when incubated with the JAK1/2 inhibitor. Together, our data suggests a mechanism for IL‐6‐mediated activation of the MR via a gp130‐JAK2/STAT3 signaling pathway. Understanding this complicated intracellular signaling pathway will allow for targeted therapies to inhibit IL‐6 induced activation of the MR and possible increases in Na+ reabsorption and hypertension.

Support or Funding Information

Emory University SUPERR 5R25DK101390‐05 to HCM; NIDDK085097 and VA MERIT I01BX002322 to RSH and 2T32DK7656‐2 to BMW

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.