Recent studies suggest a role for T lymphocytes in hypertension. However, whether T cells contribute to renal sodium retention and salt-sensitive hypertension is unknown. Here we demonstrate that T cells infiltrate into the kidney of salt-sensitive hypertensive animals. In particular, CD8+ T cells directly contact the distal convoluted tubule (DCT) in the kidneys of DOCA-salt mice and CD8+ T cell-injected mice, leading to up-regulation of the Na-Cl co-transporter NCC, p-NCC and the development of salt-sensitive hypertension. Co-culture with CD8+ T cells upregulates NCC in mouse DCT cells via ROS-induced activation of Src kinase, up-regulation of the K+ channel Kir4.1, and stimulation of the Cl− channel ClC-K. The last event increases chloride efflux, leading to compensatory chloride influx via NCC activation at the cost of increasing sodium retention. Collectively, these findings provide a mechanism for adaptive immunity involvement in the kidney defect in sodium handling and the pathogenesis of salt-sensitive hypertension.

Background: Renal T cells contribute importantly to hypertension, but the underlying mechanism is incompletely understood. We reported that CD8Ts directly stimulate distal convoluted tubule cells (DCTs) to increase sodium chloride co-transporter expression and salt reabsorption. However, the mechanistic basis of this pathogenic pathway that promotes hypertension remains to be elucidated. Methods: We used mouse models of DOCA+salt (DOCA) treatment and adoptive transfer of CD8 + T cells (CD8T) from hypertensive animals to normotensive animals in in-vivo studies. Co-culture of mouse DCTs and CD8Ts was used as in-vitro model to test the effect of CD8T activation in promoting sodium chloride co-transporter-mediated sodium retention and to identify critical molecular players contributing to the CD8T-DCT interaction. IFNγ (interferon γ)-KO mice and mice receiving renal tubule-specific knockdown of PDL1 were used to verify in-vitro findings. Blood pressure was continuously monitored via radio-biotelemetry, and kidney samples were saved at experimental end points for analysis. Results: We identified critical molecular players and demonstrated their roles in augmenting the CD8T-DCT interaction leading to salt-sensitive hypertension. We found that activated CD8Ts exhibit enhanced interaction with DCTs via IFN-γ-induced upregulation of MHC-I and PDL1 in DCTs, thereby stimulating higher expression of sodium chloride co-transporter in DCTs to cause excessive salt retention and progressive elevation of blood pressure. Eliminating IFN-γ or renal tubule-specific knockdown of PDL1 prevented T cell homing into the kidney, thereby attenuating hypertension in 2 different mouse models. Conclusions: Our results identified the role of activated CD8Ts in contributing to increased sodium retention in DCTS through the IFN-γ-PDL1 pathway. These findings provide a new mechanism for T cell involvement in the pathogenesis of hypertension and reveal novel therapeutic targets.

Alkalides with large nonlinear optical (NLO) responses exhibit broad applications in the electro-optical device field. In the present work, based on alkali (Li and Na) in conjunction with alkaline-earth (Ca) atoms doped into facially polarized all-cis 1,2,3,4,5,6-hexafluorocyclohexane (C6F6H6), we first reported two facially polarized Janus-type alkalides as an external electric field (EEF)-induced second order NLO switches M–LCaL–M (M = Li or Na, L = C6F6H6). The two 4s electrons of the Ca atom are, respectively, pushed out by the negative fluorocarbon face of one L and each of them concentrate on one alkali atom and combine with the s electron of the later to form excess electron pair. Owing to the two excess electron pairs [highest occupied molecular orbital (HOMO) and HOMO – 1], the novel alkalides M––LCa2+L–M– is formed. Interestingly, with continuous increasing of EEF magnitude, the centrosymmetric M––LCa2+L–M– bearing two excess electron pairs is obviously broken and a long-range charge transfer is exhibited gradually from one end of the alkali atom through the middle LCaL to the other end of it. Meanwhile, the influence of EEF brings a large static electronic first hyperpolarizability from 0 (EEF = 0, off form) to 59 826 (M = Li, EEF = 19 × 10–4 au, on form) or 64 231 au (M = Na, EEF = 12 × 10–4 au, on form). They also have the largest vibrational first hyperpolarizabilities (on form). These results show that alkalides M––LCa2+L–M– have potential application for NLO materials as well as exhibit advantages such as high sensitivity, being fast, and having reversible switching.

Severe renal fibrosis often occurs in obstructive kidney disease, not only in the obstructed kidney but also in the contralateral kidney, causing renal dysfunction. Although the mechanisms of injury in obstructed kidney have been studied for years, the pathogenesis of fibrosis in the contralateral kidney remains largely unknown. Here, we examined long-term unilateral ureteral obstruction (UUO) model in male Sprague–Dawley rats and found that macrophage-to-myofibroblast transition (MMT) is contributing to renal fibrosis in the contralateral kidney of UUO rats. Interestingly, this process was attenuated by treatment of eplerenone, a specific blocker of the mineralocorticoid receptor (MR). In-vitro, stimulating MR in primary cultured or cell line macrophages enhances MMT, which were also inhibited by MR blockade. Collectively, these findings provide a plausible mechanism for UUO-induced injury in the contralateral kidney, suggesting the benefit of using MR blockage as a part of treatment to UUO to protect the contralateral kidney thereby preserve renal function.