A novel role for type 1 angiotensin receptors on T lymphocytes to limit target organ damage in hypertension.
A novel role for type 1 angiotensin receptors on T lymphocytes to limit target organ damage in hypertension.
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DOI：
10.1161/circresaha.111.261768
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发表时间：
2012-06-08
影响因子：
20.1
通讯作者：
Crowley SD
中科院分区：
文献类型：
--
作者：
Zhang JD;Patel MB;Song YS;Griffiths R;Burchette J;Ruiz P;Sparks MA;Yan M;Howell DN;Gomez JA;Spurney RF;Coffman TM;Crowley SD
使用1型血管紧张素（AT 1）受体拮抗剂的人体临床试验表明，血管紧张素II是心血管和肾脏疾病的关键介质。然而，最近的研究表明，个别组织池的AT 1受体可能有不同的影响，高血压的靶器官损害。我们研究了T淋巴细胞上的AT 1受体在高血压及其并发症的发病机制中的作用。T细胞上AT 1受体的缺乏增强了高血压期间的肾损伤，使肾脏趋化因子的表达增加，并增加了T细胞在肾脏中的积聚。T淋巴细胞上缺乏AT 1受体的“T细胞敲除”小鼠的肾脏和纯化的CD 4 + T细胞增加了Th 1相关细胞因子包括IFN-γ和TNF-α的表达。在T淋巴细胞内，转录因子T-bet和加塔-3分别促进向Th 1和Th 2谱系的分化，并且AT 1受体缺陷的CD 4 + T细胞具有增强的T-bet /加塔-3表达比率，有利于诱导Th 1应答。然而，在我们的高血压模型中，由于T-bet缺乏而不能产生Th 1应答的小鼠免受肾损伤。目前的研究确定了T淋巴细胞上的AT 1受体通过有利地调节CD 4 + T辅助细胞分化在高血压背景下保护肾脏的意想不到的作用。
Human clinical trials using type 1 angiotensin (AT1) receptor antagonists indicate that angiotensin II is a critical mediator of cardiovascular and renal disease. However, recent studies have suggested that individual tissue pools of AT1 receptors may have divergent effects on target organ damage in hypertension. We examined the role of AT1 receptors on T lymphocytes in the pathogenesis of hypertension and its complications. Deficiency of AT1 receptors on T cells potentiated kidney injury during hypertension with exaggerated renal expression of chemokines and enhanced accumulation of T cells in the kidney. Kidneys and purified CD4+ T cells from “T cell knockout” mice lacking AT1 receptors on T lymphocytes had augmented expression of Th1-associated cytokines including IFN-γ and TNF-α. Within T lymphocytes, the transcription factors T-bet and GATA-3 promote differentiation toward the Th1 and Th2 lineages, respectively, and AT1 receptor-deficient CD4+ T cells had enhanced T-bet / GATA-3 expression ratios favoring induction of the Th1 response. Inversely, mice that were unable to mount a Th1 response due to T-bet deficiency were protected from kidney injury in our hypertension model. The current studies identify an unexpected role for AT1 receptors on T lymphocytes to protect the kidney in the setting of hypertension by favorably modulating CD4+ T helper cell differentiation.