Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.
Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
J Transl Med. 2021 Feb 15;19(1):69. doi: 10.1186/s12967-021-02717-5.
Acute kidney injury (AKI), with a high morbidity and mortality, is recognized as a risk factor for chronic kidney disease (CKD). AKI-CKD transition has been regarded as one of the most pressing unmet needs in renal diseases. Recently, studies have showed that salt inducible kinase 1 (SIK1) plays a role in epithelial-mesenchymal transition (EMT) and inflammation, which are the hallmarks of AKI-CKD transition. However, whether SIK1 is involved in AKI-CKD transition and by what mechanism it regulates AKI-CKD transition remains unknown.
We firstly detected the expression of SIK1 in kidney tissues of AKI patients and AKI mice by immunohistochemistry staining, and then we established Aristolochic acid (AA)-induced AKI-CKD transition model in C57BL/6 mice and HK2 cells. Subsequently, we performed immunohistochemistry staining, ELISA, real-time PCR, Western blot, immunofluorescence staining and Transwell assay to explore the role and underlying mechanism of SIK1 on AKI-CKD transition.
The expression of SIK1 was down-regulated in AKI patients, AKI mice, AA-induced AKI-CKD transition mice, and HK2 cells. Functional analysis revealed that overexpression of SIK1 alleviated AA-induced AKI-CKD transition and HK2 cells injury in vivo and in vitro. Mechanistically, we demonstrated that SIK1 mediated AA-induced AKI-CKD transition by regulating WNT/β-catenin signaling, the canonical pathway involved in EMT, inflammation and renal fibrosis. In addition, we discovered that inhibition of WNT/β-catenin pathway and its downstream transcription factor Twist1 ameliorated HK2 cells injury, delaying the progression of AKI-CKD transition.
Our study demonstrated, for the first time, a protective role of SIK1 in AKI-CKD transition by regulating WNT/β-catenin signaling pathway and its downstream transcription factor Twist1, which will provide novel insights into the prevention and treatment AKI-CKD transition in the future.
急性肾损伤（AKI）具有高发病率和死亡率，被认为是慢性肾脏病（CKD）的危险因素。AKI-CKD 转化已被认为是肾脏疾病中最紧迫的未满足需求之一。最近的研究表明，盐诱导激酶 1（SIK1）在 EMT 和炎症中发挥作用，这是 AKI-CKD 转化的标志。然而，SIK1 是否参与 AKI-CKD 转化以及它通过什么机制调节 AKI-CKD 转化尚不清楚。
我们首先通过免疫组织化学染色检测 AKI 患者和 AKI 小鼠肾脏组织中 SIK1 的表达，然后在 C57BL/6 小鼠和 HK2 细胞中建立马兜铃酸（AA）诱导的 AKI-CKD 转化模型。随后，我们进行免疫组织化学染色、ELISA、实时 PCR、Western blot、免疫荧光染色和 Transwell 测定，以探讨 SIK1 在 AKI-CKD 转化中的作用及其潜在机制。
SIK1 的表达在 AKI 患者、AKI 小鼠、AA 诱导的 AKI-CKD 转化小鼠和 HK2 细胞中下调。功能分析表明，SIK1 的过表达减轻了 AA 诱导的 AKI-CKD 转化和 HK2 细胞的损伤。机制研究表明，SIK1 通过调节 WNT/β-catenin 信号通路（参与 EMT、炎症和肾纤维化的经典通路）介导 AA 诱导的 AKI-CKD 转化。此外，我们发现抑制 WNT/β-catenin 通路及其下游转录因子 Twist1 可改善 HK2 细胞损伤，延缓 AKI-CKD 转化的进展。
我们的研究首次表明，SIK1 通过调节 WNT/β-catenin 信号通路及其下游转录因子 Twist1 在 AKI-CKD 转化中发挥保护作用，这将为未来预防和治疗 AKI-CKD 转化提供新的思路。
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