MiR-21 Mediates Fibrogenic Activation Of Pulmonary Fibroblasts And Lung Fibrosis

Liu, Gang; Abraham, Edward

doi:10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a2295

Cited by 114 publications

(203 citation statements)

References 22 publications

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“…A number of signaling pathways have been implicated in CsA nephrotoxicity and in particular, TGF‐β . Further, in the lung, miR‐21 regulates fibrosis by altering SMAD7 and thus TGF‐β function by directly reducing SMAD7 in epithelial cells . Conversely, TGF‐β itself may induce miR‐21 expression in renal epithelial cells, and blockade of SMAD3 signaling is critical in this pathway .…”

Section: Resultsmentioning

confidence: 99%

“…In cardiac fibroblasts, miR‐21 regulates the ERK–MAP kinase signaling pathway through inhibition of sprouty homologue 1 (Spry1), leading to their activation . However, in lung fibroblasts, increased miR‐21 levels promoted the pro‐fibrogenic activity of TGF‐β1 in lung fibroblasts through downregulating the expression of an inhibitory SMAD7 . This pathway is biologically sensible as prior studies have demonstrated that TGF‐β induces EMT and promotes interstitial fibrosis by regulating matrix molecule production .…”

Section: Discussionmentioning

confidence: 98%

“…These increased miR‐21 levels are associated with epithelial–mesenchymal transition in pulmonary epithelial cells . In the mouse, kidneys with unilateral ureteral obstruction express higher levels of miR‐21 than unobstructed mice , and blockade of miR‐21 in this model attenuates fibrosis . Finally, in humans, renal allografts with severe interstitial fibrosis have enhanced expression of miR‐21 compared to those without fibrosis .…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies indicate that microRNA‐21 (miR‐21) is associated with organ fibrosis in the kidney, lung, liver, and heart . For example, miR‐21 is upregulated in the experimental mice lung fibrosis as well as in lung biopsy samples in human Idiopathic pulmonary fibrosis . These increased miR‐21 levels are associated with epithelial–mesenchymal transition in pulmonary epithelial cells .…”

Section: Introductionmentioning

confidence: 99%

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Cyclosporine-mediated allograft fibrosis is associated with micro-RNA-21 through AKT signaling

et al. 2014

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SummaryCalcineurin inhibitors (CNIs) are potent immunosuppressants with associated long-term nephrotoxicity mediated by tubular epithelial cell injury and arterial vasoconstriction. We hypothesized that CNI-induced renal injury is regulated by specific microRNAs (miRNAs). In this study, we found that 46 miRNAs were significantly altered in human proximal tubular epithelial cells (HPTECs) following exposure to cyclosporine A (CsA), particularly miR-21 (5.47 AE 0.47-fold versus vehicle, P = 0.002). This increase was accompanied by alterations in epithelialmesenchymal transformation (EMT) markers including vimentin (2.80 AE 0.28-fold; P = 0.03), S100A4 (2.29 AE 0.29-fold; P = 0.04), and a-SMA (5.0 AE 0.31-fold; P = 0.03). Notably, transfection of HPTECs with miR-21 precursor also resulted in significant induction of EMT-associated genes, which were inhibited by a single-stranded nucleic acid inhibitor of miR-21. miR-21 induction resulted in a rapid increase of phosphorylated AKT and downregulation of PTEN. While CsA induces SMAD7 downregulation and TGF-b1 upregulation in HPTECs, such changes were independent of miR-21. Moreover, there was no effect on ERK phosphorylation. We confirmed these changes using a mouse model of CsA toxicity. Collectively, our results suggest that miR-21 mediates CsA nephrotoxicity via PTEN/AKT signaling pathway. Further exploration into the epigenetic response to CsA exposure may provide new therapeutic targets to ameliorate CsA nephrotoxicity.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cyclosporine-mediated allograft fibrosis is associated with micro-RNA-21 through AKT signaling

et al. 2014

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“…181 The expression of miR-21 was positively regulated by TGF-β and this induction of miR-21 subsequently repressed a disintegrin-like and metalloproteinase with thrombospondin type 1 motif (ADAMTS-1) expression while upregulating the expression of type I and III collagen. 182 Cushing et al performed a large-scale screening for miRNAs potentially involved in bleomycin-induced fibrosis and found that expression of miR-29 was significantly reduced in fibrotic lungs. 183 To investigate this finding further, this group then studied the impact of miR-29 downregulation by characterizing gene expression profiles of human fetal lung fibroblast cells in which endogenous miR-29 was knocked out.…”

Section: Ipfmentioning

confidence: 99%

Posttranscriptional control of airway inflammation

Ezegbunam

Foronjy

2017

WIREs RNA

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Acute inflammation in the lungs is a vital protective response, efficiently and swiftly eliminating inciters of tissue injury. However, in respiratory diseases characterized by chronic inflammation, such as chronic obstructive pulmonary disease and asthma, enhanced expression of inflammatory mediators leads to tissue damage and impaired lung function. Although transcription is an essential first step in the induction of proinflammatory genes, tight regulation of inflammation requires more rapid, flexible responses. Increasing evidence shows that such responses are achieved by posttranscriptional mechanisms directly affecting mRNA stability and translation initiation. RNA-binding proteins, microRNAs, and long noncoding RNAs interact with messenger RNA and each other to impact the stability and/or translation of mRNAs implicated in lung inflammation. Recent research has shown that these biological processes play a central role in the pathogenesis of several important pulmonary conditions. This review will highlight several posttranscriptional control mechanisms that influence lung inflammation and the known associations of derangements in these mechanisms with common respiratory diseases.

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Alteration of Aging‐Dependent MicroRNAs in Idiopathic Pulmonary Fibrosis

Nho

2015

Drug Development Research

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Idiopathic Pulmonary Fibrosis (IPF) is the most severe fibrotic lung disease and characterized by the accumulation of (myo)fibroblasts and collagen within the alveolar wall resulting in obliteration of the gas-exchange surface. Although the detailed pathogenesis is not understood, recent studies have found that several microRNAs (miRNAs) are associated with the progression of lung diseases including IPF. IPF is an age-associated disease and, accordingly, frequently found in an aged population. In this review, the functional roles of miRNAs that are deregulated in IPF progression are discussed together with how aging affects the miRNA signature, altering the fibroblast phenotype and promoting lung fibrosis. Finally, the possibility of targeting miRNAs as a therapeutic approach for the treatment of IPF is discussed.

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MiR-21 Mediates Fibrogenic Activation Of Pulmonary Fibroblasts And Lung Fibrosis

Cited by 114 publications

References 22 publications

Cyclosporine-mediated allograft fibrosis is associated with micro-RNA-21 through AKT signaling

Cyclosporine-mediated allograft fibrosis is associated with micro-RNA-21 through AKT signaling

Posttranscriptional control of airway inflammation

Alteration of Aging‐Dependent MicroRNAs in Idiopathic Pulmonary Fibrosis

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