MircroRNA-92b, a Novel Negative Regulator of the Transforming Growth Factor-β Signaling Pathway Targeting the Type I Receptor
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1013053 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25916502_1.fastq.gz | Fastqsanger.gz | |||
| SRR25916502_2.fastq.gz | Fastqsanger.gz | |||
| SRR25916503_1.fastq.gz | Fastqsanger.gz | |||
| SRR25916503_2.fastq.gz | Fastqsanger.gz | |||
| SRR25916504_1.fastq.gz | Fastqsanger.gz |
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Project description:Progressive renal disease is the consequence of destructive fibrosis. Renal fibrosis is a common outcome of many chronic kidney diseases, including diabetic kidney disease (DKD). Transforming growth factor-β1 (TGFβ1) has been identified as a major pathogenic factor underlying the development of DKD. It had been reported that the expression of miR-92b-3p had been reported to be reduced in the kidneys from diabetic mice and patients with DKD. However, the role of miR-92b-3p in the progress of renal fibrosis was remaining largely unknown. This study investigated the role of miR-92b-3p in the progression of renal fibrosis in unilateral ureteral occlusion (UUO) and unilateral ischemia-reperfusion injury (uIRI) mouse models, as well as explored its underlying mechanisms in human proximal tubular epithelial (HK2) cells. We found that renal fibrosis increased in UUO mice after miR-92b knockout, while reduced in miR-92b overexpressing mice. MiR-92b knockout aggravated renal fibrosis in unilateral ischemia-reperfusion injury. RNA-sequencing analysis, the luciferase reporter assay, qPCR analysis, and western blotting confirmed that miR-92b-3p directly targeted TGF-β receptor 1 (TGFBR1), thereby ameliorating renal fibrosis by suppressing the TGF-β/SMAD3 signaling pathway. Furthermore, we found that TGF-β suppressed miR-92b transcription through Snail family transcriptional repressors 1 (SNAI1) and SNAI2. Our results suggest that miR-92b-3p may serve as a novel therapeutic for mitigating fibrosis in chronic kidney disease.
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Project description:Transforming growth factor (TGF)-? signaling is deliberately regulated at multiple steps in its pathway from the extracellular microenvironment to the nucleus. However, how TGF-? signaling is activated or attenuated is not fully understood. We recently identified transmembrane prostate androgen-induced RNA (TMEPAI), which is involved in a negative feedback loop of TGF-? signaling. When we searched for a family molecule(s) for TMEPAI, we found C18ORF1, which, like TMEPAI, possesses two PY motifs and one Smad-interacting motif (SIM) domain. As expected, C18ORF1 could block TGF-? signaling but not bone morphogenetic protein signaling. C18ORF1 bound to Smad2/3 via its SIM and competed with the Smad anchor for receptor activation for Smad2/3 binding to attenuate recruitment of Smad2/3 to the TGF-? type I receptor (also termed activin receptor-like kinase 5 (ALK5)), in a similar fashion to TMEPAI. Knockdown of C18ORF1 prolonged duration of TGF-?-induced Smad2 phosphorylation and concomitantly potentiated the expression of JunB, p21, and TMEPAI mRNAs induced by TGF-?. Consistently, TGF-?-induced cell migration was enhanced by the knockdown of C18ORF1. These results indicate that the inhibitory function of C18ORF1 on TGF-? signaling is similar to that of TMEPAI. However, in contrast to TMEPAI, C18ORF1 was not induced upon TGF-? signaling. Thus, we defined C18ORF1 as a surveillant of steady state TGF-? signaling, whereas TMEPAI might help C18ORF1 to inhibit TGF-? signaling in a coordinated manner when cells are stimulated with high levels of TGF-?.
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Project description:BACKGROUND:Vascular smooth muscle cells (SMCs) synthesize extracellular matrix (ECM) that contributes to tissue remodeling after revascularization interventions. The cytokine transforming growth factor ? (TGF-?) is induced on tissue injury and regulates tissue remodeling and wound healing, but dysregulated signaling results in excess ECM deposition and fibrosis. The LIM (Lin11, Isl-1 & Mec-3) domain protein LIM domain only 7 (LMO7) is a TGF-?1 target gene in hepatoma cells, but its role in vascular physiology and fibrosis is unknown. METHODS:We use carotid ligation and femoral artery denudation models in mice with global or inducible smooth muscle-specific deletion of LMO7, and knockout, knockdown, overexpression, and mutagenesis approaches in mouse and human SMC, and human arteriovenous fistula and cardiac allograft vasculopathy samples to assess the role of LMO7 in neointima and fibrosis. RESULTS:We demonstrate that LMO7 is induced postinjury and by TGF-? in SMC in vitro. Global or SMC-specific LMO7 deletion enhanced neointimal formation, TGF-? signaling, ECM deposition, and proliferation in vascular injury models. LMO7 loss of function in human and mouse SMC enhanced ECM protein expression at baseline and after TGF-? treatment. TGF-? neutralization or receptor antagonism prevented the exacerbated neointimal formation and ECM synthesis conferred by loss of LMO7. Notably, loss of LMO7 coordinately amplified TGF-? signaling by inducing expression of Tgfb1 mRNA, TGF-? protein, ?v and ?3 integrins that promote activation of latent TGF-?, and downstream effectors SMAD3 phosphorylation and connective tissue growth factor. Mechanistically, the LMO7 LIM domain interacts with activator protein 1 transcription factor subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting activator protein 1-dependent TGF-? autoinduction. Importantly, preliminary studies suggest that LMO7 is upregulated in human intimal hyperplastic arteriovenous fistula and cardiac allograft vasculopathy samples, and inversely correlates with SMAD3 phosphorylation in cardiac allograft vasculopathy. CONCLUSIONS:LMO7 is induced by TGF-? and serves to limit vascular fibrotic responses through negative feedback regulation of the TGF-? pathway. This mechanism has important implications for intimal hyperplasia, wound healing, and fibrotic diseases.
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Project description:Transforming growth factor ?1 (TGF-?1) is a master cytokine in many biological processes, including tissue homeostasis, epithelial-to-mesenchymal transition, and wound repair. Here, we report that four and a half LIM-only protein 2 (FHL2) is a critical regulator of TGF-?1 expression. Devoid of a DNA-binding domain, FHL2 is a transcriptional cofactor that plays the role of coactivator or corepressor, depending on the cell and promoter contexts. We detected association of FHL2 with the TGF-?1 promoter, which showed higher activity in Fhl2-/- cells than in wild-type (WT) cells in a reporter assay. Overexpression of FHL2 abrogates the activation of the TGF-?1 promoter, whereas the upregulation of TGF-?1 gene transcription correlates with reduced occupancy of FHL2 on the promoter. Moreover, ablation of FHL2 facilitates recruitment of RNA polymerase II on the TGF-?1 promoter, suggesting that FHL2 may be involved in chromatin remodeling in the control of TGF-?1 gene transcription. Enhanced expression of TGF-?1 mRNA and cytokine was evidenced in the livers of Fhl2-/- mice. We tested the in vivo impact of Fhl2 loss on hepatic fibrogenesis that involves TGF-?1 activation. Fhl2-/- mice developed more severe fibrosis than their WT counterparts. These results demonstrate the repressive function of FHL2 on TGF-?1 expression and contribute to the understanding of the TGF-?-mediated fibrogenic response.
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