LAUSR

Objectives: The kidney plays a key role in salt-sensitive hypertension. Recent studies also 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 immunity and pathogenesis of salt-sensitive hypertension. Here, we propose a novel mechanism of salt-sensitive hypertension: that renal-infiltrating T cells interact with distal renal tubules, enhancing sodium retention via stimulating sodium transporter. Methods: Wild type and knockout mice were used in DOCA-salt model or T cell-adoptive transferred model. In-vitro study we co-cultured mouse distal convoluted tubule cells (DCTs) with T cells. Immuno-blot was used to detect protein expression; multi-color staining and 3D-Super-resolution SIM microscopy (Figure 1) were used to demonstrate direct interaction between cell types in-vitro and in-vivo; siRNAs were used to knockdown molecules to explore signaling pathways. Results: We found that renal infiltrated CD8 T cells interact with DCTs in the kidney via a direct cell-cell contact (Figure 1), which upregulates sodium-chloride co-transporter (NCC) in DCTs via Src kinase-induced up-regulation of the K+ channel Kir4.1, and stimulation of the Cl- channel ClC-K. The later event increases chloride efflux, leading to compensatory chloride influx via NCC activation at the cost of increasing sodium retention. Moreover, interrupting above pathway by knockout of Kir4.1 in renal tubules prevented NCC upregulation and consequent development of salt-induced salt-sensitive hypertension. Conclusion: Our 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.