Glycogen synthase kinase-3 inhibition attenuates fibroblast activation and development of fibrosis following renal ischemia/reperfusion in mice

Singh, Shailendra Pratap; Tao, Shixin; Fields, Timothy A.; Webb, S. J.; Harris, Raymond C.; Rao, Reena

doi:10.1242/dmm.020511

Cited by 52 publications

(53 citation statements)

References 64 publications

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“…Wnt/β-catenin signaling pathway plays an important role in the pathological processes involving pulmonary brosis, and suppression of wnt/β-catenin signaling could inhibit the development of pulmonary brosis [15][16][17]. GSK3β is a serine/threonine protein kinase, which promotes brogenic activity as a partaker in execution of wnt/β-catenin pathway [18][19][20]. In our current study, we discovered that inhibition of S100A2 could restrain EMT by inhibiting the wnt/β-catenin pathway.…”

Section: Discussionmentioning

confidence: 72%

Downregulation of S100A2 alleviates pulmonary fibrosis through inhibiting wnt/β-catenin signaling pathway

Huang

Zhang

Qing

et al. 2020

Preprint

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Background：Pulmonary fibrosis (PF) is a progressive and lethal disease with poor prognosis. S100A2 plays an important role in the progression of cancer. However, the role of S100A2 in PF has not been reported yet. In this study, we explored the potential role of S100A2 in PF and its potential molecular mechanisms. Methods: First, we analyzed S100A2 expression of patients with PF by retrieving RNA-sequencing datasets from Gene Expression Omnibus (GEO) database. Next, we detected the expression of S100A2 in patients with PF using quantitative real time PCR (qRT-PCR). Then, S100A2 expression was determined with or without the treatment of transforming growth factor-β1 (TGF-β1) in A549 cells. Epithelial-mesenchymal transition (EMT) biomarkers, including E-cadherin，vimentin, and α smooth muscle actin (α-SMA), were identified using qRT-PCR and western blot. Finally, the relevant signalling pathway indicators were detected by western blot. Results: Increased expression of S100A2 was first observed in lung tissues of PF patients. Meanwhile, we found that downregulation of S100A2 inhibited the TGF-β1-induced EMT in A549 cells. Mechanically, TGF-β1 up-regulated β-catenin and phosphorylation of GSK-3β, which was blocked by silencing S100A2 in vitro. Conclusion: These findings demonstrate that downregulation of S100A2 alleviate pulmonary fibrosis via inhibiting EMT. S100A2 is a promising potential target for further understanding the mechanism and developing strategy for the treatment of PF and other EMT-associated disease.

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Section: Discussionmentioning

confidence: 72%

Downregulation of S100A2 alleviates pulmonary fibrosis through inhibiting wnt/β-catenin signaling pathway

Huang

Zhang

Qing

et al. 2020

Preprint

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“…In animal models, perturbation of the Wnt/beta-catenin signaling pathway, especially GSK3-beta, appears to aggravate or ameliorate fibrosis in a variety of different tissues [34, 35]. In this pathway, beta-catenin is a key regulator which can translocate into the nucleus and bind to TCF/LEF to stimulate the transcription of Wnt target genes, including fibrosis-related genes.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis Reveals a New Benefit of Periodic Mechanical Stress on Chondrocytes

Zeng¹,

Wang²,

Xu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: In recent years, a variety of studies have been performed to investigate the cellular responses of periodic mechanical stress. In our previous studies, we found that periodic mechanical stress can promote proliferation and matrix synthesis through the integrin beta 1-mediated ERK1/2 pathway, and we used proteomic analysis to detect quantitative changes in chondrocytes under periodic mechanical stress. Despite these results, the effects and mechanisms of periodic mechanical stress are still not fully understood, so in this study we extended our study using phosphoproteomic techniques. Methods: We used phosphoproteomic techniques to detect phosphorylation changes in chondrocytes under periodic mechanical stress and combined the results with the quantitative proteomic data to further explore the underlying mechanisms. Data were obtained by phosphorylation inhibition, quantitative real-time PCR (qPCR) analysis, western blot analysis and immunofluorescence assay. Results: From phosphoproteomic analysis, a total of 1073 phosphorylated proteins and 2054 phosphopeptides were identified. The number of significant differentially expressed proteins and phosphopeptides was 97 and 108, respectively (ratio >1.20 or <0.83 at p<0.05). Periodic mechanical stress increased glycogen synthase kinase 3-beta (GSK3-beta) phosphorylation at Y216, promoted the phosphorylation of beta-catenin, decreased beta-catenin levels and suppressed the expression of type I collagen. In contrast, inhibition of GSK3-beta by TWS119, which specifically inhibits the phosphorylation of Y216, suppressed the phosphorylation of beta-catenin, which resulted in the accumulation of beta-catenin and an increase in the expression of type I collagen. Conclusions: We successfully constructed differentially expressed phosphoproteomic profiles of rat chondrocytes under periodic mechanical stress, and discovered a potential new therapeutic benefit in which periodic mechanical stress suppressed the formation of type I collagen in the matrix of chondrocytes via phosphorylation of GSK3-beta and beta-catenin.

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“…Male, 8 to 10-week-old C57Bl/6J mice (from The Jackson Laboratory) were subjected to bilateral I/R or sham surgeries as we have described before. 21 Briefly, mice were anesthetized using xylazine (10 mg/kg, IP) and ketamine (90-120 mg/ kg, IP), and injected with analgesic Buprenorphine-Sustained Release (0.5-1 mg/kg, SC). Ocular lubrication was applied.…”

Section: Induced Aki In Wild-type Micementioning

confidence: 99%

“…Quantitative real-time PCR (QRT-PCR) using cDNA prepared from RNA isolated from whole kidney and cultured cells were carried out as described previously. 21 Primer sequences are provided in Table S1. The mRNA levels were calculated relative to GAPDH levels for each sample.…”

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

“…Multiple studies including our own have demonstrated that systemic pharmacological GSK3 inhibition, or proximal tubule-specific GSK3β gene deletion can significantly reduce tubular injury, accelerate regeneration and suppress renal fibrosis following AKI in mouse models. [17][18][19][20][21][22][23] However, the mechanism by which GSK3β impedes tubular repair after AKI is unclear. We postulated GSK3β could be a regulator of FoxM1 in the AKI kidney because in glioblastoma cell lines, GSK3β phosphorylates FoxM1, which led to ubiquitination and proteolytic degradation of FoxM1 in vitro.…”

mentioning

confidence: 99%

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Glycogen synthase kinase‐3β inhibits tubular regeneration in acute kidney injury by a FoxM1‐dependent mechanism

et al. 2020

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Acute kidney injury (AKI) is characterized by injury to the tubular epithelium that leads to the sudden loss of renal function. Proper tubular regeneration is essential to prevent progression to chronic kidney disease. In this study, we examined the role of FoxM1, a forkhead box family member transcription factor in tubular repair after AKI. Renal FoxM1 expression increased after renal ischemia/reperfusion (I/R)‐induced AKI in mouse kidneys. Treatment with thiostrepton, a FoxM1 inhibitor, reduced FoxM1 regulated pro‐proliferative factors and cell proliferation in vitro, and tubular regeneration in mouse kidneys after AKI. Glycogen synthase kinase‐3 (GSK3) was found to be an upstream regulator of FoxM1 because GSK3 inhibition or renal tubular GSK3β gene deletion significantly increased FoxM1 expression, and improved tubular repair and renal function. GSK3 inactivation increased β‐catenin, Cyclin D1, and c‐Myc, and reduced cell cycle inhibitors p21 and p27. Importantly, thiostrepton treatment abolished the improved tubular repair in GSK3β knockout mice following AKI. These results demonstrate that FoxM1 is important for renal tubular regeneration following AKI and that GSK3β suppresses tubular repair by inhibiting FoxM1.

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Glycogen synthase kinase-3 inhibition attenuates fibroblast activation and development of fibrosis following renal ischemia/reperfusion in mice

Cited by 52 publications

References 64 publications

Downregulation of S100A2 alleviates pulmonary fibrosis through inhibiting wnt/β-catenin signaling pathway

Downregulation of S100A2 alleviates pulmonary fibrosis through inhibiting wnt/β-catenin signaling pathway

Proteomic Analysis Reveals a New Benefit of Periodic Mechanical Stress on Chondrocytes

Glycogen synthase kinase‐3β inhibits tubular regeneration in acute kidney injury by a FoxM1‐dependent mechanism

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