Abstract 092: Novel Mechanism of Salt-sensitive Hypertension: CD8 + T Cells Stimulate Sodium Chloride Co-transporter NCC in Kidney

Abstract

Recent studies suggest a role for T lymphocytes in hypertension. However, whether T cells contribute to renal sodium retention is an important question, which if answered, could reveal a critical relationship between adaptive immunity and pathogenesis of salt-sensitive hypertension. In the present study, we propose a novel mechanism of salt-sensitive hypertension via the distal nephron: that in salt-sensitive hypertension, renal infiltrating T cells interact with distal convoluted tubule cells (mDCTs), which leads to up-regulation of the sodium-chloride-co-transporter (NCC), and thus enhancement of sodium retention. In vivo tests used DOCA-salt mice (SBP~190mmHg on a high salt diet) and T cell-adoptive transferred mice (SBP~170mmHg on a high salt diet). Results confirmed enhanced NCC & p-NCC expression (>2.5X) in the kidneys of both mouse models. We found significantly more T cells infiltrating the kidneys of DOCA-salt & T cell-transferred mice compared to their controls. It is noteworthy that in both models a great number of CD8 + T cells (CD8Ts) in the renal tubulointerstitium surround DCT segments which have higher levels of NCC expression. Direct contact between these two cell types was confirmed by super-resolution structured illumination microscopy. In vitro, we co-cultured mDCTs with T cells, and found that CD8Ts, but not CD4Ts, significantly increased NCC expression (>3X) in mDCTs via “direct cell-cell contact”. An intracellular sodium-indicator detected higher NCC-mediated sodium uptake (>1.5X) in mDCTs treated with CD8Ts compared to untreated controls. Moreover, these effects were mediated by increased (>2.2X) functional chloride channel Clc-k in the cell membrane. Clc-k knockdown by siRNA blunted chloride efflux and abolished CD8T-induced NCC activation and sodium retention in mDCTs. Taken together, our findings suggest a novel role for CD8 + T cells in enhancement of salt retention contributing to salt-sensitive hypertension: that CD8 + T cells directly contact mDCTs, stimulate NCC by upregulating the chloride channel Clc-k on the mDCT plasma membrane, thereby increasing chloride efflux, which leads to compensatory chloride influx via NCC activation at the cost of increasing sodium influx.