Abstract 101: Interleukin 17A Upregulates Both Renal Proximal and Distal Tubule Sodium Transporters in Angiotensin II-dependent Hypertension
We have previously shown that angiotensin II (Ang II)-induced hypertension is associated with an increase in T cell production of interleukin 17A (IL17A), and that IL17A promotes hypertension and end-organ damage. However, the precise mechanism is unknown. Recently, we reported that Ang II infusion into C56Bl/6J wild type (WT) mice blunted the rate of natriuresis following an acute saline challenge, while the rate of salt and water excretion in IL17A-/- mice was unaffected by Ang II. Following 2 weeks of Ang II infusion (490 ng/kg/min), proximal tubule sodium hydrogen exchanger 3 (NHE3) abundance was depressed in IL17A-/- but not WT mice, suggesting enhanced pressure natriuresis in IL17A-/- mice. We then performed renal transporter profiling on mice deficient in IL17A, or the related isoform IL17F, after prolonged (4 weeks) of Ang II infusion (490 ng/kg/min), a time when the blood pressure reduction in IL17A-/- mice is most prominent. Interestingly, at this time, deficiency of IL17A, but not IL17F, blunted the activation of distal tubule transporters, specifically sodium-chloride cotransporter (NCC) and the epithelial sodium channel (ENaC). We hypothesized that IL17A directly modulates renal sodium transporters as a mechanism to regulate salt and water excretion and hypertension. To test this hypothesis, we treated cultured human renal proximal tubule cells and mouse distal convoluted tubule (mDCT15) cells with recombinant IL17A or IL17F. We found that IL17A, but not IL17F, increased NHE3 protein levels (1.4-fold, p=0.003) and SGK1 mRNA expression (3.9-fold, p=0.01). In mDCT15 cells, IL17A but not IL17F, increased NCC activity as measured by thiazide-inhibited sodium uptake (1.78 vs 1.62 μmol/mg/20min, p<0.001), and this increase was significantly blunted with an SGK1 inhibitor (GSK 650394) and in cells lacking Nedd4-2 (an E3 ubiquitin ligase downstream of SGK1). Moreover, in mDCT15 cells, acute IL17A treatment caused phosphorylation of SGK1 on Ser78. These studies are the first to describe a mechanistic link by which IL17A modulates renal sodium transporters and suggests that targeting IL17A may improve renal function and slow the progression to renal failure in hypertension and other autoimmune disorders.
Author Disclosures: A.E. Norlander: None. N. Kamat: None. B. Ko: None. A. Kirabo: None. J. Gnecco: None. M.A. Saleh: None. R.S. Hoover: None. A. McDonough: None. M.S. Madhur: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Modest; Gilead. C. Other Research Support (includes receipt of drugs, supplies, equipment or other in-kind support); Modest; Amgen.
- © 2015 by American Heart Association, Inc.