Klotho mitigates cyclosporine A (CsA)-induced epithelial–mesenchymal transition (EMT) and renal fibrosis in rats

Liu, Qifeng; Ye, Jianming; Liu, Yu; Dong, Xiaohong; Jiang, Feng; Xiong, Yan; Gu, Xiaoxia; Li, Shasha

doi:10.1007/s11255-016-1439-0

Cited by 32 publications

(26 citation statements)

References 26 publications

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“…A and Table S2). Several lines of evidences previously showed that mesenchymal markers were upregulated upon CsA treatment . Considering the negative regulation of miRNAs on target genes, we postulate that the downregulated miRNAs may probably participate in CsA‐induced EMT.…”

Section: Resultsmentioning

confidence: 77%

“…It has been suggested that EMT contributes to CsA‐induced renal damage and fibrosis . We postulated that miR‐181c may participate in this process.…”

Section: Resultsmentioning

confidence: 90%

“…Liu et al . disclosed that Klotho significantly inhibited CsA‐induced renal lesions by modulating EMT‐associated proteins. Recently, EMT was reported to be a strong predictor of graft function decline in renal transplant recipients exposed to CsA .…”

mentioning

confidence: 99%

“…Shin et al [8] demonstrated that Nrf2 played a protective role against CsA-induced renal fibrosis by inhibiting EMT genes. Liu et al [9] disclosed that Klotho significantly inhibited CsA-induced renal lesions by modulating EMT-associated proteins. Recently, EMT was reported to be a strong predictor of graft function decline in renal transplant recipients exposed to CsA [10].…”

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confidence: 99%

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miR‐181c protects CsA‐induced renal damage and fibrosis through inhibiting EMT

Sun

Min

et al. 2017

FEBS Letters

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Cyclosporine A (CsA), a widely used immunosuppressive drug in organ transplantation and autoimmune disorders, frequently induces renal damage and fibrosis. Recent evidence has implicated epithelial-mesenchymal transition (EMT) in CsA-induced nephrotoxicity. Microarray analysis disclosed miR-181c as the microRNA most dramatically repressed by CsA. Downregulation of miR-181c expression at the transcriptional level by CsA is dependent on the transcription factor Nrf2. miR-181c mimics or inhibitors attenuate or aggravate CsA-induced EMT gene changes, respectively. Importantly, in Nrf2-/- mice, CsA-induced renal damage, fibrosis, and EMT gene changes are restored by miR-181c mimics. Mechanistically, we identified Notch2 as a potential target of miR-181c. Collectively, our data support the notion that miR-181c may serve as an important factor for protecting renal tissues from CsA-induced nephrotoxicity.

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Section: Resultsmentioning

confidence: 77%

“…It has been suggested that EMT contributes to CsA‐induced renal damage and fibrosis . We postulated that miR‐181c may participate in this process.…”

Section: Resultsmentioning

confidence: 90%

mentioning

confidence: 99%

mentioning

confidence: 99%

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miR‐181c protects CsA‐induced renal damage and fibrosis through inhibiting EMT

Sun

Min

et al. 2017

FEBS Letters

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“…This means that TGF-1 may regulate oxidative stress, which occurs during the process of tissue repair/remodelling and fibrosis (Babalola, Mamalis, Lev-Tov, & Jagdeo, 2014; Barnes & Gorin 2011;Bataller et al, 2003), to result in tissue fibrosis. Recently, epithelial-to-mesenchymal transition (EMT) was reported to be associated with tissue fibrosis by driving the production of numerous ECM proteins (Liu et al, 2017a;Zhang et al, 2018). TNF-, an important pro-inflammatory factor during chronic tissue injury and inflammation, can stimulate uncontrolled ECM protein deposition, ultimately resulting in fibrosis and organ failure (Thakur, Pritchard, McMullen, & Nagy, 2006).…”

Section: Introductionmentioning

confidence: 99%

Hydrogen inhalation attenuated bleomycin‐induced pulmonary fibrosis by inhibiting transforming growth factor‐β1 and relevant oxidative stress and epithelial‐to‐mesenchymal transition

Gao

Jiang

Geng

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?The aim was to explore the effects and underlying mechanisms of H2 on bleomycin‐induced pulmonary fibrosis. What are the main findings and its importance?Our results indicate that, in bleomycin‐induced pulmonary fibrosis, H2 inhalation attenuated oxidative stress and reversed the pulmonary epithelial‐to‐mesenchymal transition process by reducing reactive oxygen species production and inhibiting the expression of transforming growth factor‐β1, α‐smooth muscle actin and collagen I to improve fibrotic injury and exert anti‐fibrogenic effects. Thus, H2 inhalation has promising therapeutic potential as a useful adjuvant treatment for patients with idiopathic pulmonary fibrosis, which deserves further study and evaluation. Abstract Hydrogen (H2) can protect against tissue damage. The effect of H2 inhalation therapy on the pathogenesis of pulmonary fibrosis remains unknown. This study was designed to explore the effects and underlying mechanisms of H2 inhalation on bleomycin (BLM)‐induced pulmonary fibrosis. A rat model of pulmonary fibrosis was established with BLM. Rats were randomly divided into control and H2 inhalation groups. Haematoxylin and Eosin staining and Mason's Trichrome staining were performed to evaluate pulmonary fibrosis injury, inflammatory cell infiltration, structural disorder and collagen deposition. qRT‐PCR and western blot assays were used to determine the expression of TNF‐α, TGF‐β1, α‐SMA, E‐cadherin, N‐cadherin, vimentin, VEGF and collagen type I at both mRNA and protein levels. The contents of reactive oxygen species, TGF‐β1, TNF‐α, malondialdehyde and hydroxyproline were determined with biochemical test kits or ELISA kits. Bleomycin‐stimulated rats exhibited typical symptoms of pulmonary fibrosis, which featured an increase in collagen deposition, alveolitis, fibrosis and parenchymal structural disorder in the lung. However, BLM‐induced oxidative stress was attenuated by H2 inhalation therapy, which reduced the contents of reactive oxygen species, malondialdehyde and hydroxyproline, enhanced the activity of glutathione peroxidase and decreased the expression of TGF‐β1 and TNF‐α. In addition, H2 inhalation also inhibited BLM‐induced epithelial‐to‐mesenchymal transition by inhibiting TGF‐β1, increasing the expression level of the epithelial cell marker E‐cadherin, and decreasing the expression level of the mesenchymal cell marker vimentin in a time‐dependent manner. In addition, H2 inhalation downregulated α‐SMA expression and suppressed collagen I generation, exerting anti‐fibrogenic effects. Hydrogen inhalation therapy attenuates BLM‐induced pulmonary fibrosis by inhibiting TGF‐β1, relevant oxidative stress and epithelial‐to‐mesenchymal transition.

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A PDE1 inhibitor, vinpocetine, ameliorates epithelial-mesenchymal transition and renal fibrosis in adenine-induced chronic kidney injury in rats by targeting the DNMT1/Klotho/β-catenin/Snail 1 and MMP-7 pathways

Abdelfattah,

Mohammed,

Talaat

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Tubulointerstitial fibrosis (TIF) is present with chronic kidney disease (CKD). Vinpocetine (Vinpo) is used for treating cerebrovascular deficits, exhibiting some kidney-beneficial effects; however, its role in TIF is uncertain. So, the aim of this study was to investigate its potential impact on adenine-induced fibrotic CKD and explore the underlying mechanistic aspects. Eighteen male Wistar rats were categorized into three groups (n = 6 each). Group I was kept as controls and given saline; group II received adenine (300 mg/kg, twice weekly, i.p.) for induction of the CKD model; and group III was administered Vinpo (20 mg/kg/d, orally) concurrently with adenine. All treatments were administered for 4 weeks. Vinpo revealed an improvement in renal function and an alleviation of inflammation triggered by adenine via diminishing serum tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels. Further, Vinpo repressed the epithelial-mesenchymal transition (EMT) with preserved E-cadherin mRNA expression and lowered gene and immune expression of fibronectin and vimentin, respectively, besides attenuating the elevated G2/M arrest-related molecules (renal Ki67 protein contents and p21 gene expression). Renal pathological alterations caused by adenine were attenuated upon Vinpo administration. Interestingly, Vinpo suppressed abnormal renal β-catenin immunoreactivity, Snail 1, and MMP-7 gene expression while simultaneously restored Klotho protein expression by downregulating DNA methyltransferase 1 enzyme (DNMT1) protein expression in the kidney. These data indicated that Vinpo effectively mitigated EMT and G2/M arrest-induced renal fibrosis in adenine-induced CKD rats by targeting DNMT1-associated Klotho suppression, subsequently inhibiting β-catenin and its fibrotic downstream genes.

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Klotho mitigates cyclosporine A (CsA)-induced epithelial–mesenchymal transition (EMT) and renal fibrosis in rats

Abstract: Klotho inhibits CsA-induced EMT and renal fibrosis in rats. Klotho may serve as a therapeutic agent to minimize CsA-induced renal fibrosis.

Cited by 32 publications

References 26 publications

miR‐181c protects CsA‐induced renal damage and fibrosis through inhibiting EMT

miR‐181c protects CsA‐induced renal damage and fibrosis through inhibiting EMT

Hydrogen inhalation attenuated bleomycin‐induced pulmonary fibrosis by inhibiting transforming growth factor‐β1 and relevant oxidative stress and epithelial‐to‐mesenchymal transition

A PDE1 inhibitor, vinpocetine, ameliorates epithelial-mesenchymal transition and renal fibrosis in adenine-induced chronic kidney injury in rats by targeting the DNMT1/Klotho/β-catenin/Snail 1 and MMP-7 pathways

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