Role of Calcineurin Isoforms in Renal Regulation of Blood Pressure

项目总结： 大约3100万美国人患有慢性肾脏疾病，其特征是 肾功能进行性下降。慢性肾脏病的主要致病因素之一是高 血压或高血压。尽管有几类降压药，但血压仍然 超过一半的患者不受控制。这突显了需要新的药物靶点。的一个特点 血压不受控制是指肾脏钠处理失调。肾脏对钠的处理是 全身盐分和水分平衡的基石，以及随后的血压动态平衡。细胞内 调节肾脏钠转运体表达和/或活性的机制为下一步的研究提供了新的方向 一代又一代血压疗法。 通过将细胞和分子生物学与动物模型相结合，我们的长期研究目标是 识别和开发调节肾脏钠转运体和随后钠离子的信号通路 手感和血压。钙调神经磷酸酶(CNA)是一种新的调节肾脏钠处理和 已被确认与高血压有关。此外，临床和实验数据支持一个角色 对于CNA在调节肾脏钠转运体和血压方面的作用。与文献中描述的一致， 初步研究表明，用他克莫司(普通抑制剂)抑制CNA可刺激血管紧张素转换酶的上调 肾脏氯化钠共转运体(NCC)。然而，对NCC潜在机制的理解 调节、肾脏钠处理和血压控制受到以下方面的知识空白的限制 每种肾脏cna异构体(cnaα和cnaβ)的具体作用。 这项R21拨款将描绘出每个CNA亚型对血压调节的贡献。对这件事 最后，我们利用了创新的转基因小鼠模型和细胞系。这笔R21赠款的结果是 将增进我们对cna异构体调节血压的具体机制的了解 并为抗高血压和免疫抑制疗法的发展提供信息。

PROJECT SUMMARY: Approximately 31 million Americans suffer from Chronic Kidney Disease, which is characterized by a progressive decline in kidney function. One of the major contributing factors to Chronic Kidney Disease is high blood pressure or hypertension. Despite several classes of anti-hypertensive drugs, blood pressure remains uncontrolled in more than half of patients. This underscores the need for new drug targets. A feature of uncontrolled blood pressure is dysregulated renal sodium handling. Sodium handling by the kidney is the cornerstone of whole body salt and water balance, and subsequent blood pressure homeostasis. Intracellular mechanisms that regulate renal sodium transporter expression and/or activity offer a new direction for the next generation of blood pressure therapies. By integrating cellular and molecular biology with animal models, our long-term research objective is to identify and exploit signaling pathways that regulate renal sodium transporters and subsequently sodium handling and blood pressure. Calcineurin (CnA) is a new player in the regulation of renal sodium handling and has been identified to be involved in hypertension. Furthermore, clinical and experimental data support a role for CnA in regulation of renal sodium transporters and blood pressure. Consistent with the literature, preliminary studies show that CnA inhibition with tacrolimus (general inhibitor) stimulates the upregulation of the renal sodium chloride cotransporter (NCC). However, understanding of the underlying mechanisms of NCC regulation, renal sodium handling and blood pressure control are limited by a gap in knowledge regarding the specific role of each renal CnA isoform (CnAα and CnAβ). This R21 grant will delineate the contribution of each CnA isoform to blood pressure regulation. To this end, we take advantage of innovative transgenic mouse models and cell lines. The outcomes of this R21 grant will enhance our knowledge of the specific mechanisms by which CnA isoforms regulate blood pressure as well as inform the development of anti-hypertensive and immunosuppressive therapies.