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Hypertension. 2016 Jul;68(1):167-74. doi: 10.1161/HYPERTENSIONAHA.116.07493. Epub 2016 May 2.

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

Author information

1
From the Departments of Molecular Physiology and Biophysics (A.E.N., B.L.D., M.S.M.) and Microbiology, Immunology, and Pathology (J.G.), Vanderbilt University, Nashville, TN; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.A.S., L.Z., M.S.M.); Faculty of Pharmacy, Department of Pharmacology and Toxicology, Mansoura University, Mansoura, Egypt (M.A.S.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (N.V.K., A.A.M.D.); Department of Medicine, Chicago University School of Medicine, IL (B.K.); Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan (Y.I.); and Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.H.).

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.

KEYWORDS:

angiotensin II; blood pressure; hypertension; interleukin 17; kidney

PMID:
27141060
PMCID:
PMC4900947
DOI:
10.1161/HYPERTENSIONAHA.116.07493
[Indexed for MEDLINE]
Free PMC Article

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