Novel mechanism of salt‐sensitive hypertension: CD8 + T cells stimulate sodium chloride co‐transporter NCC in kidney

The key role of the kidney in the development of salt‐sensitive hypertension has been demonstrated by many laboratories, and excessive sodium reabsorption by the distal nephron is a key contributor to this disease. 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 directly 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≈190 mmHg on a high salt diet) and T cell‐adoptive transferred mice (SBP≈170 mmHg on a high salt diet). Results confirmed enhanced NCC & p‐NCC expression (>2X) 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 ( Figure 1). In vitro, we co‐cultured mDCTs with T cells, and found that CD8Ts, but not CD4Ts, significantly increased NCC expression (>2.5X) in mDCTs via direct cell‐cell contact. Using co‐culture inserts with 0.4 mm pore size membrane to prohibit direct contact between these two cell types prevented CD8T‐induced NCC up‐regulation in mDCTs. In a function study, 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 ROS‐induced activation of Src kinase (>1.5X), up‐regulation of the K + channel Kir4.1 (>2X), and stimulation of the Cl − channel ClC‐K (>2X) to increase chloride efflux. Taken together, our findings suggest a novel role for CD8 + T cells in enhancement of salt retention in kidney: that CD8 + T cells directly contact DCTs, activate ROS‐Src signal, stimulate NCC by upregulating the Kir4.1‐Clc‐k pathway 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 ( Figure 2). These findings provide a novel mechanism for involvement of adaptive immunity in the kidney defect in sodium handling, which contributes to the pathogenesis of salt‐sensitive hypertension. Support or Funding Information Funding: American Heart Association Beginning Grant‐in‐Aid 15BGIA25730047 (Mu);Support: Dr. Philip Palade and the University of Arkansas for Medical Sciences Foundation (Mu) 13D‐Super‐resolution structured illumination microscopy image: in the kidney of DOCA‐salt mice (Similar result also obtained from adoptive CD8 + T cell transfer recipient mice), CD8 + T cell (CD8, red) direct contact with the basolateral side of the distal convoluted tubule (Na‐K‐ATPase, cyan, basolateral membrane marker) stimulating NCC (green) expression on apical side of DCTs. (DAPI, dark blue)2Scheme of a hypothetical mechanism in kidney for the pathogenesis of salt‐sensitive hypertension.