Ample genetic and physiological evidence establishes that renal salt handling is a critical regulator of blood pressure. Studies also establish a role for the immune system, T-cell infiltration and immune cytokines in hypertension. This study aimed to connect immune cytokines, specifically IFN-γ and IL-17A, to sodium transporter regulation in the kidney during angiotensin II (AngII) hypertension. C57BL/6J (wild type, WT) mice, responded to AngII infusion (490 ng/kg/min, 2 weeks) with a rise in blood pressure (to 170 mmHg) and a significant decrease in the rate of excretion of a saline challenge. In comparison, mice that lacked the ability to produce either IFN-γ (IFN-γ−/−) or IL-17A (IL-17A−/−) exhibited a blunted rise in blood pressure (to <150 mmHg), and both genotypes maintained baseline diuretic and natriuretic responses to a saline challenge. Along the distal nephron, AngII infusion increased abundance of the phosphorylated forms of the Na-K-2Cl cotransporter, Na-Cl cotransporter and Ste20/SPS-1 related proline-alanine rich kinase, in both the WT and IL-17A−/− but not in IFN-γ−/− mice; epithelial Na channel abundance increased similarly in all three genotypes. In the proximal nephron, AngII infusion significantly decreased abundance of Na/H-exchanger isoform 3 and the motor myosin VI in IL-17A−/− and IFN-γ−/− , but not WT; the Na-phosphate cotransporter decreased in all three genotypes. Our results suggest that during AngII hypertension both IFN-γ and IL-17A production interfere with the pressure natriuretic decrease in proximal tubule sodium transport and that IFN-γ production is necessary to activate distal sodium reabsorption.

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.

Efficient oxygen utilization in the kidney may be supported by paracellular epithelial transport, a form of passive diffusion that is driven by preexisting transepithelial electrochemical gradients. Claudins are tight-junction transmembrane proteins that act as paracellular ion channels in epithelial cells. In the proximal tubule (PT) of the kidney, claudin-2 mediates paracellular sodium reabsorption. Here, we used murine models to investigate the role of claudin-2 in maintaining energy efficiency in the kidney. We found that claudin-2-null mice conserve sodium to the same extent as WT mice, even during profound dietary sodium depletion, as a result of the upregulation of transcellular Na-K-2Cl transport activity in the thick ascending limb of Henle. We hypothesized that shifting sodium transport to transcellular pathways would lead to increased whole-kidney oxygen consumption. Indeed, compared with control animals, oxygen consumption in the kidneys of claudin-2-null mice was markedly increased, resulting in medullary hypoxia. Furthermore, tubular injury in kidneys subjected to bilateral renal ischemia-reperfusion injury was more severe in the absence of claudin-2. Our results indicate that paracellular transport in the PT is required for efficient utilization of oxygen in the service of sodium transport. We speculate that paracellular permeability may have evolved as a general strategy in epithelial tissues to maximize energy efficiency.