The IFNγ-PDL1 Pathway Enhances CD8T-DCT Interaction to Promote Hypertension.
The IFNγ-PDL1 Pathway Enhances CD8T-DCT Interaction to Promote Hypertension.
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DOI：
10.1161/circresaha.121.320373
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发表时间：
2022-05-13
影响因子：
20.1
通讯作者：
Mu S
中科院分区：
文献类型：
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作者：
Benson LN;Liu Y;Wang X;Xiong Y;Rhee SW;Guo Y;Deck KS;Mora CJ;Li LX;Huang L;Andrews JT;Qin Z;Hoover RS;Ko B;Williams RM;Heller DA;Jaimes EA;Mu S
肾 T 细胞对高血压有重要影响，但其潜在机制尚不完全清楚。我们报道 CD8T 直接刺激远端曲管细胞 (DCT) 以增加氯化钠协同转运蛋白 (NCC) 表达和盐重吸收。然而，这种促进高血压的致病途径的机制基础仍有待阐明。我们在体内研究中使用 DOCA+盐 (DOCA) 治疗的小鼠模型以及将 CD8+ T 细胞 (CD8T) 从高血压动物过继转移至血压正常动物。使用小鼠远曲小管细胞 (mDCT) 和 CD8T 的共培养作为体外模型，测试 CD8T 激活在促进 NCC 介导的钠潴留中的作用，并确定有助于 CD8T-DCT 相互作用的关键分子参与者。使用 IFNγ-KO 小鼠和接受肾小管特异性敲除 PDL1 的小鼠来验证体外研究结果。通过无线电生物遥测技术连续监测血压，并在实验终点保存肾脏样本以供分析。我们确定了关键分子参与者并证明了它们在增强 CD8T-DCT 相互作用导致盐敏感性高血压中的作用。我们发现，活化的CD8Ts通过IFNγ诱导的DCTs中MHC-I和PDL1的上调表现出与DCTs的相互作用增强，从而刺激DCTs中NCC的更高表达，导致过度盐潴留和血压逐渐升高。消除 IFNγ 或肾小管特异性敲低 PDL1 可阻止 T 细胞归巢至肾脏，从而减轻两种不同小鼠模型中的高血压。我们的结果确定了活化的 CD8T 通过 IFNγ-PDL1 途径促进 DCTS 钠潴留的作用。这些发现为T细胞参与高血压发病机制提供了新机制，并揭示了新的治疗靶点。
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 (NCC) expression and salt reabsorption. However, the mechanistic basis of this pathogenic pathway that promotes hypertension remains to be elucidated. 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 distal convoluted tubule cells (mDCTs) and CD8Ts was used as in-vitro model to test the effect of CD8T activation in promoting NCC-mediated sodium retention and to identify critical molecular players contributing to the CD8T-DCT interaction. IFNγ-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 endpoints for analysis. 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 IFNγ-induced upregulation of MHC-I and PDL1 in DCTs, thereby stimulating higher expression of NCC in DCTs to cause excessive salt retention and progressive elevation of blood pressure. Eliminating IFNγ or renal tubule-specific knockdown of PDL1 prevented T cell homing into the kidney, thereby attenuating hypertension in two different mouse models. Our results identified the role of activated CD8Ts in contributing to increased sodium retention in DCTS through the IFNγ-PDL1 pathway. These findings provide a new mechanism for T cell involvement in the pathogenesis of hypertension and reveal novel therapeutic targets.