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

Abstract

Angiotensin II (Ang 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 (NHE3) expression after 2 weeks of Ang II infusion compared to wild type (WT) 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, a 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 (NCC) and the epithelial sodium channel (ENaC) and protected mice from glomerular and tubular injury. In human proximal tubule (HK-2) cells, IL-17A increased NHE3 expression through a serum and glucocorticoid regulated kinase 1 (SGK1) dependent pathway. In mouse distal convoluted tubule (mDCT15) cells, IL-17A increased NCC activity in an SGK1/Nedd4-2 dependent pathway. In both cell types, acute treatment with IL-17A induced phosphorylation of SGK1 at serine 78, and treatment with an SGK1 inhibitor blocked the effects of IL-17A on NHE3 and NCC. Interestingly, both HK-2 and mDCT15 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.

Oxidative Stress and Hypertensive Diseases

“…160 Recent data indicate that IL17A modulates expression and function of the sodium hydrogen exchanger 3 and sodium chloride cotransporter in renal tubular epithelial cells, thus promoting sodium reuptake by these cells. 161 IL-17A also promotes aortic stiffening and directly stimulates production of collagen by aortic fibroblasts. 162 …”

A salt-sensing kinase in T lymphocytes, SGK1, drives hypertension and hypertensive end-organ damage

“…Albuminuria is a well-known marker of glomerular injury and has been shown to increase following Ang II infusion in WT C57BL/6J mice (4,6). For these experiments, we used tg CD4cre mice as a secondary control.…”

“…Evidence from our group and others has demonstrated that hypertension is an inflammatory disease characterized by T cell activation, infiltration of target organs such as the kidney and vasculature, and production of cytokines that lead to salt and water retention, vascular dysfunction, and renal injury (3)(4)(5)(6).…”

“…Recently, we showed that IL-17A regulates proximal and distal renal sodium transporters and contributes to Ang II-induced renal injury (6). IL-17A is produced by subsets of CD4 + T helper cells (Th17 cells), CD8 + cytotoxic T cells (Tc17 cells), and innate-like gamma delta T cells (γδT17 cells).…”

ISN Forefronts Symposium 2015: Maintaining Balance Under Pressure—Hypertension and the Proximal Tubule

“…Interestingly, the study also demonstrated that IL-17A stimulated NHE3 expression in cultured kidney cells mediated by serum and glucocorticoid regulated kinase 1 phosphorylation. 59 …”