PDF(Pubmed)
Abstract：
Chronic kidney disease (CKD) is a major worldwide public health problem. The increase in the number of patients with CKD and end-stage kidney disease requesting renal dialysis or transplantation will progress to epidemic proportions in the next several decades. Although blocking the renin-angiotensin system (RAS) has been used as a first-line standard therapy in patients with hypertension and CKD, patients still progress towards end-stage kidney disease, which might be closely associated with compensatory renin expression subsequent to RAS blockade through a homeostatic mechanism. The Wnt/β-catenin signalling pathway is the master upstream regulator that controls multiple intrarenal RAS genes. As Wnt/β-catenin regulates multiple RAS genes, we inferred that this pathway might also be implicated in blood pressure control. Therefore, discovering new medications to synchronously target multiple RAS genes is necessary and essential for the effective treatment of patients with CKD. We hypothesized that Shenkang injection (SKI), which is widely used to treat CKD patients, might ameliorate CKD by inhibiting the activation of multiple RAS genes via the Wnt/β-catenin signalling pathway. To test this hypothesis, we used adenine-induced CKD rats and angiotensin II (AngII)-induced HK-2 and NRK-49F cells. Treatment with SKI inhibited renal function decline, hypertension and renal fibrosis. Mechanistically, SKI abrogated the increased protein expression of multiple RAS elements, including angiotensin-converting enzyme and angiotensin II type 1 receptor, as well as Wnt1, β-catenin and downstream target genes, including Snail1, Twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1 and fibroblast-specific protein 1, in adenine-induced rats, which was verified in AngII-induced HK-2 and NRK-49F cells. Similarly, our results further indicated that treatment with rhein isolated from SKI attenuated renal function decline and epithelial-to-mesenchymal transition and repressed RAS activation and the hyperactive Wnt/β-catenin signalling pathway in both adenine-induced rats and AngII-induced HK-2 and NRK-49F cells. This study first revealed that SKI repressed epithelial-to-mesenchymal transition by synchronously targeting multiple RAS elements by blocking the hyperactive Wnt/β-catenin signalling pathway.
摘要：
慢性肾脏病(CKD)是全球性的重大公共卫生问题。在接下来的几十年中，要求肾透析或移植的CKD和终末期肾脏疾病患者数量的增加将发展到流行程度。尽管阻断肾素-血管紧张素系统（RAS）已被用作高血压和CKD患者的一线标准治疗，患者仍进展为终末期肾病，通过稳态机制，这可能与RAS阻断后的补偿性肾素表达密切相关。Wnt/β-连环蛋白信号通路是控制多个肾内RAS基因的主要上游调节因子。由于Wnt/β-catenin调节多个RAS基因，我们推断这条途径也可能与血压控制有关.因此,发现同步靶向多种RAS基因的新药物对于CKD患者的有效治疗是必要和必要的.我们假设肾康注射液(SKI)，广泛用于治疗CKD患者，可能通过Wnt/β-catenin信号通路抑制多种RAS基因的激活来改善CKD。为了检验这个假设，我们使用腺嘌呤诱导的CKD大鼠和血管紧张素II（AngII）诱导的HK-2和NRK-49F细胞。用SKI治疗抑制肾功能下降，高血压和肾纤维化。机械上,SKI消除了多个RAS元件的蛋白质表达增加，包括血管紧张素转换酶和血管紧张素II1型受体，以及Wnt1、β-catenin和下游靶基因，包括Snail1、Twist、在腺嘌呤诱导的大鼠中，基质金属蛋白酶-7，纤溶酶原激活物抑制剂-1和成纤维细胞特异性蛋白1，这在AngII诱导的HK-2和NRK-49F细胞中得到证实。同样，我们的结果进一步表明,在腺嘌呤诱导的大鼠和AngII诱导的HK-2和NRK-49F细胞中,用SKI分离的大黄酸治疗可减弱肾功能下降和上皮-间质转化,抑制RAS激活和过度活跃的Wnt/β-catenin信号通路.这项研究首次揭示了SKI通过阻断过度活跃的Wnt/β-catenin信号通路同步靶向多个RAS元件来抑制上皮-间质转化。
