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

Hypertension is a leading cause of cardiovascular disease morbidity and mortality. Yet, the pathogenesis of hypertension is still poorly understood, and despite conventional treatment, blood pressure (BP) remains uncontrolled in nearly half of the hypertensive population. Emerging evidence from our group and others implicates innate and adaptive immune cells and the cytokines that they produce as pathogenic mediators of this disease and its attendant end-organ damage. Interleukin-17A (IL-17A), a proinflammatory cytokine produced predominantly by CD4 T-helper 17 cells as well as γ δ T cells, plays an important role in numerous autoimmune diseases. We have shown that in response to angiotensin II (Ang II) infusion, mice deficient in IL-17A develop an initial increase in BP that is similar to wild-type (WT) mice but are unable to sustain these elevated pressures. BP starts to decline after 2 weeks and is ≈30 mm Hg lower than Ang II–infused WT mice by 4 weeks. Moreover, IL-17A mice exhibit reduced vascular inflammation and preserved vascular function in response to Ang II infusion compared with WT mice. In keeping with this, Amador et al reported a marked increase in T-helper 17 cells in deoxycorticosterone acetate–salt treated rats and observed that treating deoxycorticosterone acetate–salt rats with an antibody against IL-17A reduced BP and collagen deposition in the heart and kidneys. We recently showed that Ang II–treated IL-17A mice have preserved diuresis and natriuresis in response to an acute saline challenge unlike Ang II–treated WT mice, which retain salt and water. Consistent with this finding, proximal tubule sodium hydrogen exchanger 3 (NHE3) protein abundance was reduced 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. (Hypertension. 2016;68:00-00. DOI: 10.1161/HYPERTENSIONAHA.116.07493.) • Online Data Supplement