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Melatonin ameliorates renal fibroblast-myofibroblast transdifferentiation and renal fibrosis through miR-21-5p regulation.

ABSTRACT: Fibroblast-myofibroblast transdifferentiation (FMT) is widely recognized as the major pathological feature of renal fibrosis. Although melatonin has exerted antifibrogenic activity in many diseases, its role in renal FMT remains unclear. In the present study, the aim was to explore the effect of melatonin on renal FMT and the underlying mechanisms. We established the transforming growth factor (TGF)-?1 stimulated rat renal fibroblast cells (NRK-49F) model in vitro and unilateral ureteral obstruction (UUO) mice model in vivo. We assessed levels of ?-smooth muscle actin (?-SMA), col1a1 and fibronectin, STAT3 and AP-1, as well as miR-21-5p and its target genes (Spry1, PTEN, Smurf2 and PDCD4). We found that melatonin reduced the expression of ?-SMA, col1a1 and fibronectin, as well as the formation of ?-SMA filament in TGF-?1-treated NRK-49F cells. Meanwhile, melatonin inhibited STAT3 phosphorylation, down-regulated miR-21-5p expression, and up-regulated Spry1 and PTEN expression. Moreover, miR-21-5p mimics partially antagonized the anti-fibrotic effect of melatonin. For animal experiments, the results revealed that melatonin remarkably ameliorated UUO-induced renal fibrosis, attenuated the expression of miR-21-5p and pro-fibrotic proteins and elevated Spry1 and PTEN expression. Nevertheless, agomir of miR-21-5p blocked the renoprotective effect of melatonin in UUO mice. These results indicated that melatonin could alleviate TGF-?1-induced renal FMT and UUO-induced renal fibrosis through down-regulation of miR-21-5p. Regulation of miR-21-5p/PTEN and/or miR-21-5p/Spry1 signal might be involved in the anti-fibrotic effect of melatonin in the kidneys of UUO mice.

SUBMITTER: Li N

PROVIDER: S-EPMC7214152 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Melatonin ameliorates renal fibroblast-myofibroblast transdifferentiation and renal fibrosis through miR-21-5p regulation.

Li Ningning N Wang Zhan Z Gao Fenglan F Lei Yanfei Y Li Zhenzhen Z

Journal of cellular and molecular medicine 20200403 10

Fibroblast-myofibroblast transdifferentiation (FMT) is widely recognized as the major pathological feature of renal fibrosis. Although melatonin has exerted antifibrogenic activity in many diseases, its role in renal FMT remains unclear. In the present study, the aim was to explore the effect of melatonin on renal FMT and the underlying mechanisms. We established the transforming growth factor (TGF)-β1 stimulated rat renal fibroblast cells (NRK-49F) model in vitro and unilateral ureteral obstruc ...[more]

PMID: 32243691

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Project description:BACKGROUND: Tumour stromal myofibroblasts can promote tumour invasion. As these cells are genetically more stable than cancer cells, there has been enormous interest in developing targeted molecular therapies against them. Chloride intracellular channel 4 (CLIC4) and reactive oxygen species (ROS) have been linked with promoting stromal cell transdifferentiation in various cancers, but little is known of their roles in ovarian cancer. In this study, we examined the functional roles that both CLIC4 and ROS play in the process of ovarian cancer cell-stimulated or TGF-beta1 induced fibroblast-to-myofibroblast transdifferentiation. We also examine whether it is possible to reverse such a process, with the aim of developing novel therapies against ovarian cancer by targeting activated transdifferentiated myofibroblasts. RESULTS: We demonstrate that TGF-beta1 induced or CM(SKOV3) activate transdifferentiated myofibroblasts (fibroblasts). These fibroblasts mimic "reactive" stromal myofibroblasts and demonstrate significant up-regulation of CLIC4 expression and increased level of ROS production. Blocking the production of ROS with an antioxidant consequently reduces the expression of CLIC4, and is accompanied by disappearance of alpha-smooth-muscle actin (alpha-SMA), a myofibroblast marker, suggesting ROS acts as a signalling molecule that promotes and enhances CLIC4 activities in the myofibroblast transdifferentiaton process. Down-regulation of CLIC4 with a generic agent or specific siRNA both significantly reduces the expression of factors related to the phenotypes and functions of myofibroblasts, such as alpha-SMA, hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), thus reversing the myofibroblast phenotype back to fibroblasts. These results convincingly show that ROS and CLIC4 are responsible for TGF-beta1 induced fibroblast-to-myofibroblast transdifferentiaton and down-regulation of both is sufficient to block transdifferentiated myofibroblasts. CONCLUSION: Molecular targeting of ROS and CLIC4 has the potential to develop novel therapies for ovarian cancer.

Dataset Information

Melatonin ameliorates renal fibroblast-myofibroblast transdifferentiation and renal fibrosis through miR-21-5p regulation.

Publications

Melatonin ameliorates renal fibroblast-myofibroblast transdifferentiation and renal fibrosis through miR-21-5p regulation.

Similar Datasets

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