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

Norlander AE, Saleh MA, Kamat NV, Ko B, Gnecco J, Zhu L, Dale BL, Iwakura Y, Hoover RS, McDonough AA, Madhur MS
Hypertension. 2016 68 (1): 167-74

PMID: 27141060 · PMCID: PMC4900947 · DOI:10.1161/HYPERTENSIONAHA.116.07493

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.

© 2016 American Heart Association, Inc.

MeSH Terms (19)

Acute Kidney Injury Analysis of Variance Angiotensin II Animals Blood Pressure Determination Cells, Cultured Disease Models, Animal Hypertension Immunoblotting Interleukin-17 Kidney Tubules, Proximal Male Mice Mice, Inbred C57BL Random Allocation Real-Time Polymerase Chain Reaction Sensitivity and Specificity Sodium Chloride Symporters Solute Carrier Family 12, Member 3

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