The Relationship Between Acute Kidney Injury (AKI) And Chronic Kidney Disease (CKD)
Mar 25, 2022
Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com
PART Ⅱ: Role of SIK1 in the transition of acute kidney injury into chronic kidney disease
Jinxiu Hul, JiaoQiaot, Qun Yul, Bing Liu1 & et al.
Abstract
Background: Acute kidney injury (AKI), with high morbidity and mortality, is recognized as a risk factor for chronic kidney disease (CKD). AKI-CKD(Acute kidney injury to chronic kidney disease) transition has been regarded as one of the most pressing unmet needs in renal diseases. Recently, studies have shown that salt inducible kinase 1 (SIK1) plays a role in epithelial-mesenchymal transition (EMT) and inflammation, which are the hallmarks of AKI-CKD(Acute kidney injury to chronic kidney disease) transition. However, whether SIK1 is involved in AKI-CKD(Acute kidney injury to chronic kidney disease) transition and by what mechanism it regulates AKI-CKD(Acute kidney injury to chronic kidney disease) transition remains unknown.
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Methods: We firstly detected the expression of SIK1 in kidney tissues of AKl patients and AKI mice by immunogens-to chemistry stamina and then we established Aristolochic acid (AA)-induced AK-CK)transition model in (57BI /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(Acute kidney injury to chronic kidney disease) transition.
Results: The expression of SIK1 was down-regulated in AKI patients, AKI mice, AA-induced AKI-CKD(Acute kidney injury to chronic kidney disease) transition mice, and HK2 cells. Functional analysis revealed that overexpression of SIK1 alleviated AA-induced AKI-CKD(Acute kidney injury to chronic kidney disease) transition and HK2 cells injury in vivo and in vitro. Mechanistically, we demonstrated that SIK1(salt inducible kinase 1) mediated AA-induced AKI-CKD(Acute kidney injury to chronic kidney disease) transition by regulating WNT/β-catenin signaling, the canonical pathway involved in EMT, inflammation and renal fibrosis. In addition, we discovered that inhibition of the WNI/β-catenin pathway and its downstream transcription factor Iwist1 ameliorated HK2 cells injury, delaying the progression of AKI-CKD(Acute kidney injury to chronic kidney disease) transition.
Conclusions: Our study demonstrated, for the first time, a protective role of SIK1in AK-CKD(Acute kidney injury to chronic kidney disease) transition by regulating the WNT/β-catenin signaling pathway and its downstream transcription factor Twist1, which will provide novel insights into the prevention and treatment of AKI-CKD(Acute kidney injury to chronic kidney disease) transition in the future.
Keywords: AA. SIK1.AKI-CKD(Acute kidney injury to chronic kidney disease) transition. Wnt/B-catenin, Twist1
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Discussion
AKI(Acute kidney injury) is a serious public health problem with high morbidity and mortality. In the past, AKI(Acute kidney injury) was considered to be reversible and a temporary decline in renal function. However, recent studies have gradually realized that the recovery of renal function in patients who survive AKI(Acute kidney injury) is often incomplete [23-25]. A meta-analysis has reported that patients with AKI(Acute kidney injury) had higher risks for developing CKD(chronic kidney disease) and ESDR, compared with patients without AKI(Acute kidney injury) [26]. Recently, the mechanism of AKI-CKD(Acute kidney injury to chronic kidney disease) transition has attracted more and more attention from nephrologists. Many factors such as nephron loss, vascular insufficiency, endothelial injury, cell cycle disruption, interstitial inflammation and fibrosis, and maladaptive repair mechanisms may lead to the evolution of AKI(Acute kidney injury) into CKD [27]. The pathophysiological mechanisms are as follows:(1)After AKI(Acute kidney injury), inflammatory cells release inflammatory factors and chemokines, and continuous inflammation can lead to the loss of renal function [28];(2) Nephron loss, endothelial injury, vascular malfunction, leading to ischemia and hypoxia of renal tubular microenvironment and fibrosis of tubular interstitial [27];(3)After AKI(Acute kidney injury), tubular epithelial cell undergo EMT to produce myofibroblasts from the epithelia to heal the injured tissues. If the injury is mild and acute, the healing process is considered as reparative fibrosis; However, under continuous chronic inflammation, the abnormal formation of myofibroblasts can lead to progressive fibrosis, after which ECM accumulation and then the destruction of organ parenchyma will occur [29];(4)The cell cycle G2/M was arrested in renal tubular epithelial cells after AKI(Acute kidney injury), which can activate pro-fibrotic signaling pathway to induce profibrotic cytokine production [30]. In this study, we used AA to mimic the progression of AKI-CKD(Acute kidney injury to chronic kidney disease) transition in vivo and in vitro, and we observed that AA stimulation can induce inflammation, EMT and fibrosis, which suggests the successful establishment of AKI-CKD(Acute kidney injury to chronic kidney disease) transition model.
Abundant evidence has demonstrated the role of SIK1 on EMT [8-10] and inflammation [1, 31], which are the hallmarks of AKI-CKD(Acute kidney injury to chronic kidney disease) transition. For instance,it was reported that the LKB1-SIK1 signaling pathway inhibited EMT by regulating the expression of some key transcription factors, including Snail2, Twist and ZEB1 [32]. More recently, the role of SIK1 in kidney damage has drawn considerable attention. Ferrandi et al.have reported that nephrin and SIK1 co-localization in glomerular podocytes and there is a positive correlation between nephrin and SIK1 protein expression in rats and human renal specimens[12]. Moreover, SIK1 is involved in high glucose-induced mesangial cell proliferation and extracellular matrix accumulation mediated by the ALK5 signaling pathway [6]. All above indicate that SIK1 has a vital role in kidney damage. SIK1 has a highly conserved serine(Thrl82)in the kinase domain. After being activated by the AMPK-activator LKB1 which phosphorylates SIK1 at Thrl82, the activated SIK1 auto-phosphorylates its Ser186, and then maintains the sustained activity of SIK1 through sequential phosphorylation at Serl86-Thr182 by GSK-3β [33].In this study, we discovered that the expression of SIK1 was downregulated in AKI(Acute kidney injury) patients and AKI(Acute kidney injury) mice, arousing our interest to further explore whether SIK1 was involved in AKI-CKD(Acute kidney injury to chronic kidney disease) transition. By assessing the level of SIK1 in HK2 cells and C57BL/6 mice treated with AA, we observed that SIK1 and p-SIK1(Thr182) were down-regulated upon AA stimulation. The correlation of the decreased activity of SIK1 with its protein level under AA treatment is consistent with findings in HBZY-1 cells in which the level of Thr182 phosphorylation correlated with the SIK1 protein level under stimulation with high glucose [6]. What's more,in the current study, we revealed the nuclear redistribution of SIK1 following AA stimulation in HK2 cells, which may result from the reduction in SIK1 kinase activity [6,34,35]. Further work is required to characterize the mechanism by which AA localizes SIK1 in the nucleus. Furthermore, we identified that overexpression of SIK1 delayed the progression of inflammation, EMT and fibrosis induced by AA both in vivo and in vitro. Thus, we concluded that AA induces AKI-CKD(Acute kidney injury to chronic kidney disease) transition by inhibiting SIK1 and its phosphorylation level.
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Multiple intracellular signal transduction pathways are involved in the expression and activation of EMT and renal fibrosis, including the TGF-β signaling pathway, PI3K/AKT pathway, Src pathway, MAPK pathway, and WNT signaling pathway [36-41].Among these, the WNT/β-catenin signaling pathway, the most classic WNT pathway, was widely studied. Abundant data have suggested that WNT/β-catenin signaling plays a vital role in EMT [42,43], inflammation [44,45] and renal fibrosis [46-48].β-catenin, a multifunctional protein, is the core molecular in the WNT signaling pathway. When there is no WNT signal stimulation,β-catenin is mainly connected to the proximal C-terminal domain of E-cadherin in the cell membrane; when stimulated by WNT signal, β-catenin translocates into the nucleus and binds to TCF/LEF transcription factors to stimulate the transcription of WNT target genes [49,50]. The phosphorylation of β-catenin(Y654)leads to its release from E-cadherin protein and increases TCF-mediated transcriptional activity, balancing its role between cell adhesion and WNT signaling [51]. In addition, the increased phosphorylation level ofβ-catenin(Y654) can increase cell migration and induce tumor cell invasion [52]. In this study, we found that AA stimulation activated the WNT/β-catenin signaling pathway and enhanced the transcriptional activity of TCF and LEF. In addition, we observed knockdown of β-catenin alleviated the inflammatory response, EMT and fibrosis induced by AA, suggesting that the WNT/β-catenin signaling pathway is involved in AKI-CKD(Acute kidney injury to chronic kidney disease) transition, which was consistent with a previous study [17]. Furthermore, we discovered SIK1 regulated WNT/β-catenin signaling pathway both in vivo and in vitro, further supporting the role of SIK1 in AA-induced AKI-CKD(Acute kidney injury to chronic kidney disease) transition.
EMT and renal fibrosis require a powerful transcription mechanism to regulate. The transcription factors that activate EMT and fibrosis are mainly divided into three major groups: Snail transcription factors, ZEB transcription factors and bHLH transcription factors. Snail is a zinc finger protein that acts as a transcriptional repressor by recognizing the E-box in the promoter of the target gene and the increased expression of Snail is involved in EMT [53]. Similar to the effect of Snail, Twist1 down-regulated the expression of epithelial phenotype-related genes and induced the expression of mesenchymal phenotype-related genes [54]. The role of Snail and Twist1 in the process of AA-induced AKI-CKD(Acute kidney injury to chronic kidney disease) transition is still not fully understood. In this study, we found AA pro-moted the protein and mRNA expression of Snail and Twist while knockdown β-catenin inhibited the expression of Snail and Twist1 induced by AA. Furthermore, we observed that silenced Twistl by siRNA alleviated the occurrence of EMT and the progression of renal fibrosis induced by AA, suggesting Twistl plays an important role in AA-induced AKI-CKD(Acute kidney injury to chronic kidney disease) transition. Further studies are required to determine whether SIK1 could regulate the expression of Twistl during AKI-CKD(Acute kidney injury to chronic kidney disease) transition.
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Conclusion
In this study, we demonstrated that SIK1 was involved in the AA-induced AKI-CKD(Acute kidney injury to chronic kidney disease) transition, and we showed that SIK1 participated in AKI-CKD(Acute kidney injury to chronic kidney disease) transition through the WNT/β-catenin signaling pathway (Fig. 9). Upregulation of SIK1, or inhibition of WNT/β-catenin signaling pathway alleviates the inflammation, EMT, and fibrosis induced by AA, delaying the progression of AKI-CKD(Acute kidney injury to chronic kidney disease) transition. These observations will provide a new therapeutic target for the clinical prevention and treatment of renal fibrosis after AKI(Acute kidney injury).
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