Interleukin‐6 Activates the Sodium Chloride Cotransporter via the Janus Kinase (Jak)/Signal Transducer and Activator of Signaling (STAT)
Authors: Wynne Brandi Michele , Moyer Hayley Catherine , Hecht Gillian Grace , Krishnamurthy Ashwini , Ko Benjamin , Hoover Robert S. 
Published: June 2021

Hypertension is characterized by increased sodium (Na+) reabsorption along the aldosterone‐sensitive distal nephron (ASDN) as well as chronic systemic inflammation and increased cytokines such as interleukin‐6 (IL‐6). Interestingly, increased Na+ reabsorption within the ASDN does not always correlate with increases in serum 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.We have previously shown that IL‐6 can increase thiazide‐sensitive 22Na+ uptake in an in vitro model of mDCT15 cells, via MR and Rac1/ROS mechanisms. Additionally, we have shown that intra‐renal infusion of IL‐6 increases phosphor(T53) NCC and total NCC, in vivo. However, we have yet to define the mechanisms linking IL‐6 receptor a (IL‐6Ra) binding and NCC activation. The Janus Kinase (Jak)/Signal Transducer and Activator of Transcription (STAT) signaling pathway has been previously implicated in IL‐6‐mediated renal pathology. We hypothesize that IL‐6 can transactivate the MR, increasing Na+ reabsorption via the Jak/STAT signaling pathway.Using mDCT15 cell monolayers, we performed thiazide‐sensitive 22Na+‐uptake studies. Increased 22Na+ uptake (n=3/group) was observed with IL‐6 incubation (100 ng/mL) as compared to vehicle (1666±12 vs. 1449±7 nmol/mg, p<0.0001). This increase was reduced with the addition of the gp130 inhibitor (1534±13 nmol/mg, p<0.001; SC144 [2μM]) or the Jak3/STAT3 inhibitor (1500±18 nmol/mg, p<0.0001; curcubitacin [10μM]). Interestingly, inhibition with the selective STAT3 inhibitor (NSC74859) or the Jak1/2 inhibitor (Ruxoltinib) did not significantly reduce the IL‐6‐mediated increases in 22Na+ uptake. When experiments were performed in the presence of the HSP90 inhibitor, which would not allow for MR activation, this response was also reduced (1499±12 nmol/mg; p<0.0001).We also confirmed that intra‐renal IL‐6 activates IL‐6Ra, in vivo, using intra‐renal IL‐6 infusion (16 ng/hr, 0.1% BSA in saline; 3 days) or vehicle. Jugular catheters were attached to a miniosmotic pump and inserted under the renal capsule. Mice were sacrificed, tissues removed and cryosectioned for immunofluorescence (IF) studies. We observed a significant increase in basolateral gp130 protein expression after 3 days of IL‐6 intra‐renal infusion. Together, our data suggest that IL‐6 activates the gp130 subunit, leading to Jak/STAT activation and thiazide‐sensitive Na+ uptake.Support or Funding InformationEmory SIRE to GGH and BMW; ASPET SURF to GGH; Emory University SUPERR 5R25DK101390‐05 to HCM; NIDDK P01‐DK‐56788 to BK, NIDDK085097 and VA MERIT I01BX002322 to RSH and 2T32DK7656‐2 to BMWThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.