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.

Rationale Accumulating evidence supports a role of adaptive immunity and particularly T cells in the pathogenesis of hypertension. Formation of memory T cells, which requires the co-stimulatory molecule CD70 on antigen presenting cells, is a cardinal feature of adaptive immunity. Objective To test the hypothesis that CD70 and immunological memory contribute to the blood pressure elevation and renal dysfunction mediated by repeated hypertensive challenges. Methods and Results We imposed repeated hypertensive challenges using either L-NAME/high salt or repeated ang II stimulation in mice. During these challenges effector memory T (TEM) cells accumulated in the kidney and bone marrow. In the L-NAME/high salt model, memory T cells of the kidney were predominant sources of IFN-γ and IL-17A, known to contribute to hypertension. L-NAME/high salt increased macrophage and dendritic cell surface expression of CD70 by 3 to 5-fold. Mice lacking CD70 did not accumulate TEM cells and did not develop hypertension to either high salt or the second ang II challenge and were protected against renal damage. Bone marrow residing TEM cells proliferated and redistributed to the kidney in response to repeated salt feeding. Adoptively transferred TEM cells from hypertensive mice homed to the bone marrow and spleen and expanded upon salt feeding of the recipient mice. Conclusions Our findings illustrate a previously undefined role of CD70 and long-lived TEM cells in the development of blood pressure elevation and end-organ damage that occur upon delayed exposure to mild hypertensive stimuli. Interventions to prevent repeated hypertensive surges could attenuate formation of hypertension-specific TEM cells.

No abstract