Abstract
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.
Highlights
Recent studies suggest a role for T lymphocytes in hypertension
A role for the immune system in hypertension was proposed in the 1960s and is supported by the following observations: Immuno-compromised nude mice are less able to maintain hypertension in response to DOCA-salt treatment compared with immuno-competent mice[33]; thymus transplantation from WKY rats to SHR lowers blood pressure in SHR34; and dysfunction of immune cells caused by Rag-1 knockout/mutation or the immunosuppressant mycophenolate-mofetil blunts the elevated blood pressure in DOCA-salt treated animals or Dahl salt-sensitive rats[35,36,37]
To determine whether T cells are involved in the up-regulation of NCC in distal convoluted tubule (DCT) cells, we extracted pan T cells (CD3 þ, Fig. 1b left) from spleens of C57B6 mice and co-cultured them with mDCT15 cells, an established cell model of mouse DCT44
Summary
Recent studies suggest a role for T lymphocytes in hypertension. whether T cells contribute to renal sodium retention and salt-sensitive hypertension is unknown. These results suggested that TK-treatment induces higher mDCT membrane expression and activation of ClC-K, which may be responsible for the higher chloride efflux from mDCTs. To confirm the role of ClC-K in TK-mediated chloride efflux from mDCTs and its relation to TK-NCC-mediated sodium retention, we used both ClC-K1 and ClC-K2 siRNAs to knock down ClC-K (Supplementary Fig. 14b,c).
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