Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II-Induced Hypertension

• Type of Material: Article
• Authors: Allison E. Norlander, Vanderbilt University; Mohammed A. Saleh, Vanderbilt University; Nikhil V. Kamat, University of Southern California; Benjamin Ko, University of Chicago; Juan Gnecco, Vanderbilt University; Linjue Zhu, Vanderbilt University; Bethany L. Dale, Vanderbilt University; Yoichiro Iwakura, Tokyo University of Science; Robert Hoover Jr, Emory University; Alicia A. McDonough, University of Southern California; Meena S. Madhur, Vanderbilt University
• Language: English
• Date: 2016-07-01
• Publisher: Lippincott Williams & Wilkins
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.07493
• Title of Journal or Parent Work: Hypertension
• Volume: 68
• Issue: 1
• Start Page: 167
• End Page: +
• Grant/Funding Information: This work was supported by a training grant from the National Institutes of Health (NIH T32 HL069765-11A1) to AEN, an American Heart Association (AHA) Post-doctoral Fellowship Award (14POST20420025) to MAS, an AHA GIA (15GRNT23160003) and an NIH NIDDK R01 (DK083785) to AMcD, an NIH NHLBI K08 award (HL121671) to MSM, and support from the National Center for Research Resources, Grant UL1 RR024975-01, now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06.; And an NIH NIDDK R01 (DK083785) to AMcD, an NIH NHLBI K08 award (HL121671) to MSM, and support from the National Center for Research Resources, Grant UL1 RR024975-01, now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06.
• Keywords: Cardiovascular System & Cardiology; Cytokine; T-cell; Mice; interleukin 17; Science & Technology; angiotensin II; Peripheral Vascular Disease; Vascular dysfunction; blood pressure; hypertension; Organ damage; Cotransporter; Life Sciences & Biomedicine; Pathway; Epithelial cells; Expression; kidney; Family
• Research Categories: Biology, Cell; Biology, Neuroscience; Biology, Molecular; Biophysics, Medical; Health Sciences, Toxicology; Biology, Microbiology; Health Sciences, Pharmacology

Abstract

Angiotensin II-induced hypertension is associated with an increase in T-cell production of interleukin-17A (IL-17A). Recently, we reported that IL-17A-/- mice exhibit blunted hypertension, preserved natriuresis in response to a saline challenge, and decreased renal sodium hydrogen exchanger 3 expression after 2 weeks of angiotensin II infusion compared with wild-type mice. In the current study, we performed renal transporter profiling in mice deficient in IL-17A or the related isoform, IL-17F, after 4 weeks of Ang II infusion, the time when the blood pressure reduction in IL-17A-/- mice is most prominent. Deficiency of IL-17A abolished the activation of distal tubule transporters, specifically the sodium-chloride cotransporter and the epithelial sodium channel and protected mice from glomerular and tubular injury. In human proximal tubule (HK-2) cells, IL-17A increased sodium hydrogen exchanger 3 expression through a serum and glucocorticoid-regulated kinase 1-dependent pathway. In mouse distal convoluted tubule cells, IL-17A increased sodium-chloride cotransporter activity in a serum and glucocorticoid-regulated kinase 1/Nedd4-2-dependent pathway. In both cell types, acute treatment with IL-17A induced phosphorylation of serum and glucocorticoid-regulated kinase 1 at serine 78, and treatment with a serum and glucocorticoid-regulated kinase 1 inhibitor blocked the effects of IL-17A on sodium hydrogen exchanger 3 and sodium-chloride cotransporter. Interestingly, both HK-2 and mouse distal convoluted tubule 15 cells produce endogenous IL-17A. IL17F had little or no effect on blood pressure or renal sodium transporter abundance. These studies provide a mechanistic link by which IL-17A modulates renal sodium transport and suggest that IL-17A inhibition may improve renal function in hypertension and other autoimmune disorders.