Wnt/β-catenin signaling and renin-angiotensin system in chronic kidney disease.
Wnt/β-catenin signaling and renin-angiotensin system in chronic kidney disease.
复制标题
慢性肾脏病中的 Wnt/β-连环蛋白信号传导和肾素-血管紧张素系统
DOI：
10.1097/mnh.0000000000000205
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发表时间：
2016-03
影响因子：
3.2
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Zhou L;Liu Y
肾内肾素-血管紧张素系统（RAS）的激活在高血压和慢性肾脏病（CKD）的发病机制中起重要作用。然而，RAS基因在体内是如何调节的，直到最近才被了解得很少。本文就RAS基因转录调控的最新研究进展及其在CKD治疗中的应用作一综述。生物信息学分析揭示了所有RAS基因的启动子区域中存在T细胞因子（TCF）/β-连环蛋白的推定结合位点。体外和体内研究均证实，Wnt/β-连环蛋白是控制肾脏中所有检测的RAS组分（如血管紧张素原、肾素、血管紧张素转换酶（ACE）和血管紧张素II I型受体（AT 1））表达的主要上游调节因子。通过小分子ICG-001或内源性Wnt拮抗剂Klotho靶向抑制Wnt/β-连环蛋白，抑制RAS激活并改善蛋白尿和肾损伤。Wnt/β-连环蛋白信号传导的阻断也使CKD小鼠模型中的血压正常化。这些最近的研究确定Wnt/β-catenin是控制多个RAS基因的主要调节因子，并表明靶向这种上游信号传导可能是治疗高血压和CKD患者的有效策略。
Intrarenal activation of the renin–angiotensin system (RAS) plays an essential role in the pathogenesis of hypertension and chronic kidney diseases (CKD). However, how RAS genes are regulated in vivo was poorly understood until recently. This review focuses on recent findings of the transcriptional regulation of RAS components as well as their implication in developing novel strategies to treat the patients with CKD. Bioinformatics analyses have uncovered the presence of putative binding sites for T cell factor (TCF)/β-catenin in the promoter region of all RAS genes. Both in vitro and in vivo studies confirm that Wnt/β-catenin is the master upstream regulator that controls the expression of all RAS components tested such as angiotensinogen, renin, angiotensin converting enzyme (ACE) and angiotensin II type I receptor (AT1) in the kidney. Targeted inhibition of Wnt/β-catenin, by either small molecule ICG-001 or endogenous Wnt antagonist Klotho, represses RAS activation and ameliorates proteinuria and kidney injury. Blockade of Wnt/β-catenin signaling also normalizes blood pressure in mouse model of CKD. These recent studies identify Wnt/β-catenin as the master regulator that controls multiple RAS genes, and suggest that targeting this upstream signaling could be an effective strategy for the treatment of patients with hypertension and CKD.