基于Kelch-like 3/WNK通路探讨缓激肽对肾脏远曲小管钠氯协同转运体的作用及机制

Hypertension is a major global concern. Activity of Na-Cl cotransporter (NCC) in renal distal convoluted tubule plays a vital role in regulating blood pressure and renal sodium, potassium and acid-base metabolism. Previous studies showed that mutation of Kelch-like3 (KLHL3) at s433 site activated NCC by regulating degradation of WNK. Our previous findings demonstrated that Calcineurin (CaN) was phosphatase of KLHL3-S433-P, and CaN inhibitor increased NCC activity via KLHL3/WNK pathway. However, what is the physiological activator of CaN needs further study. Bradykinin (BK) is also vital for blood pressure regulation. BK was reported to inhibit NCC activity. However, the mechanism was obscure. BK was reported to be tightly associated with intracellular calcium, calmodulin, which are usually CaN-dependent. So we hypothesized that BK might be the physiological activator of CaN and regulate NCC activity by KLHL3/WNK pathway. In this study, we will explore the mechanisms of NCC activity regulation by BK based on KLHL3/WNK pathway.

高血压是威胁人类健康的重要疾病，而肾脏钠氯协同转运体(NCC)在调节血压和肾脏离子转运中起着关键作用。研究证实Kelch样蛋白3(KLHL3)突变可激活NCC。我们前期研究显示钙调磷酸酶(CaN)是KLHL3的磷酸酶，抑制CaN可通过KLHL3/WNK途径激活NCC，然而什么是CaN的生理性激动剂尚不明确。缓激肽(BK)在血压调解中也扮演了重要的角色，既往研究显示BK可抑制NCC活性，但其机制尚未明确。同时，BK与细胞内钙水平，钙调蛋白等有着广泛的联系，而这些信号途径往往是CaN依赖的。因此我们推测BK可能作为CaN的生理性激动剂通过KLHL3/WNK途径来调节NCC活性。本项目将在前期研究基础上，通过动物实验和细胞实验探讨KLHL3/WNK途径在BK调节NCC活性中的作用。旨在阐明BK在NCC介导的血压调节中的分子机制，发展新的高血压治疗靶点，为临床上治疗高血压提供新思路。

慢性肾脏病（Chronic Kidney disease，CKD）已经成为全球威胁人类健康的重要疾病，且CKD的早治疗、早干预是延缓CKD进展的重要策略。钙磷代谢紊乱是CKD的重要并发症及病情进展的重要危险因素。本项目研究结果发现(1)在高血压肾损害大鼠模型的早期，即使没有出现明显的肾功能异常及血磷异常，反映单个肾单位磷负荷的磷排泄分数（FEp）已明显升高；（2）肾单位磷负荷通过形成钙-磷微结晶造成肾脏组织炎症损害；（3）给予肠道磷结合剂干预后可显著减轻肾脏组织炎症改变；（4）临床患者数据显示，早在CKD2期部分患者已经出现了明显的FEp增加；（5）腺嘌呤诱导的CKD动物模型实验显示CKD早期给予磷负荷干预可以改善CKD的临床指标并延缓CKD进展；（6）补体C1q、Ccl2/MCP-1相关代谢通路参与了磷负荷导致的肾脏损害。基于以上发现，本项目观察了高血压肾损害早期磷负荷造成肾脏损害的机制，且探讨了CKD早期干预肾脏磷负荷对CKD进展的影响及磷负荷诱导的单核-巨噬细胞趋化相关分子机制，结合CKD病人临床数据，探究CKD钙磷代谢紊乱干预时机，为临床延缓CKD进展的治疗提供新的理论依据和思路。

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