Abstract 004: Interleukin 17a Regulates Salt And Water Retention Through Enhanced Sgk1 And Nhe3 Expression In The Renal Proximal Tubule
We have previously shown that the pro-inflammatory cytokine, interleukin 17A (IL17A), is upregulated by angiotensin II and plays a critical role in promoting angiotensin II-induced hypertension and vascular dysfunction. However, the mechanism by which IL17A promotes hypertension is not known. Our preliminary studies demonstrated that angiotensin II-induced hypertension decreased sodium hydrogen exchanger 3 (NHE3) in the kidneys of IL17A-/- mice to a greater extent than in wild type (WT) mice. This likely enhances the pressure natriuresis in these mice and could explain the lower hypertensive response to angiotensin II in these animals. Serum glucocorticoid kinase 1 (SGK1) potentially regulates NHE3 in the kidney. Therefore, we hypothesized that IL17A upregulates SGK1 and NHE3 in the renal proximal tubule and that loss of IL17A would enhance natriuresis and diuresis. Using cultured human proximal tubule cells (HK-2 cells), we found that IL17A upregulated SGK1 mRNA expression 3.9±0.4 fold (n=4, p<.0001). In vivo, angiotensin II infusion upregulated renal SGK1 mRNA expression in wild type (WT) mice 2.6±0.3 fold, and this effect was abolished in IL17A deficient mice (n=3-4, p=.02). Upregulation of renal SGK1 expression in WT mice was specific to the cortex. Further, we found that IL17A induced phosphorylation of SGK1 at Ser78 2.01±0.4 fold (p=0.08, n=4) in HK-2 cells after 15 minutes. This effect was prevented when the cells were pretreated with a p38 inhibitor. We also found that NHE3 protein was upregulated 4±0.6 fold (n=2) by IL17A in these cells, suggesting a potential connection between phosphorylated SGK1 and NHE3 upregulation. Finally, we demonstrated that WT mice, in response to an intraperitoneal saline challenge, retained an additional 28.6% of the injected volume (p<.01), 32.7% of sodium (p<.01) and 30.7% of chloride (p<.05) after 10 days of angiotensin II infusion, and this effect was abolished in IL17A-/- mice (n=5-6), indicative of preserved natriuresis and diuresis in these mice. These studies are the first to describe a link between IL17A and the induction of renal SGK1 and NHE3 and thus provide a potential mechanism by which IL17A modulates salt and water retention and ultimately blood pressure.
Author Disclosures: A.E. Norlander: None. A. Kirabo: None. J. Gnecco: None. N. Kamat: None. M.A. Saleh: None. A. McDonough: None. D.G. Harrison: None. M.S. Madhur: None.
- © 2014 by American Heart Association, Inc.