Protective Role of Estrogen-induced miRNA-29 Expression in Carbon Tetrachloride-induced Mouse Liver Injury

Zhang, Yaqin; Wu, Ling-Ling; Wang, Yan; Zhang, Mingcao; Liu, Limin; Zhu, Dunru; Li, Xi-Han; Gu, Hang; Zhang, Chenyu; Zen, Ke

doi:10.1074/jbc.m111.314922

Cited by 98 publications

(75 citation statements)

References 47 publications

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“…Other investigators reported the modulation of other miRNAs by glucocorticoids and TGF-b. 38,39 Although the mechanism underlying the regulation of miR-30 by glucocorticoids or TGF-b remains unknown at this stage, our previous finding that TGF-b reduces miR-29a/b level in IAR20 cells through increasing the level of nuclear NF-kB p65 40 may imply that TGF-b can also reduce miR-30 level via upregulating the NF-kB signaling pathway in podocytes.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of MicroRNA-30 Facilitates Podocyte Injury and Is Prevented by Glucocorticoids

Cai

Fan

et al. 2014

Journal of the American Society of Nephrology

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MicroRNAs (miRNAs) are essential for podocyte homeostasis, and the miR-30 family may be responsible for this action. However, the exact roles and clinical relevance of miR-30s remain unknown. In this study, we examined the expression of the miR-30 family in the podocytes of patients with FSGS and found that all members are downregulated. Treating cultured human podocytes with TGF-b, LPS, or puromycin aminonucleoside (PAN) also downregulated the miR-30 family. Podocyte cytoskeletal damage and apoptosis caused by treatment with TGF-b or PAN were ameliorated by exogenous miR-30 expression and aggravated by miR-30 knockdown. Moreover, we found that miR-30s exert their protective roles by direct inhibition of Notch1 and p53, which mediate podocyte injury. In rats, treatment with PAN substantially downregulated podocyte miR-30s and induced proteinuria and podocyte injury; however, transfer of exogenous miR-30a to podocytes of PAN-treated rats ameliorated proteinuria and podocyte injury and reduced Notch1 activation. Finally, we demonstrated that glucocorticoid treatment maintains miR-30 expression in cultured podocytes treated with TGF-b, LPS, or PAN and in the podocytes of PAN-treated rats. Glucocorticoid-sustained miR-30 expression associated with reduced Notch1 activation and alleviated podocyte damage. Taken together, these findings demonstrate that miR-30s protect podocytes by targeting Notch1 and p53 and that the loss of miR-30s facilitates podocyte injury. In addition, sustained miR-30 expression may be a novel mechanism underlying the therapeutic effectiveness of glucocorticoids in treating podocytopathy.

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Section: Discussionmentioning

confidence: 99%

Downregulation of MicroRNA-30 Facilitates Podocyte Injury and Is Prevented by Glucocorticoids

Cai

Fan

et al. 2014

Journal of the American Society of Nephrology

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155

143

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“…The miR-29 family contains three members miR-29a, miR-29b, and miR-29c, all of which are transcriptionally induced by p53 [68] and repressed by c-Myc, NF-κB, and TGF-β signaling ( see [69]). Functionally, miR-29 serves to reduce cell proliferation by targeting CDK6 [70–71], to induce cell senescence or differentiation by targeting Ppmid [68] or osteonectin [72], respectively, and to stimulate cell apoptosis by targeting Mcl1 and Bcl2 [73–74].…”

Section: Regulation Of Mirnas In Carcinomasmentioning

confidence: 99%

Choice of antiretroviral therapy differentially impacts survival of HIV-infected CD4 T cells

et al. 2014

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BackgroundHIV eradication strategies are now being evaluated in vitro and in vivo. A cornerstone of such approaches is maximal suppression of viral replication with combination antiretroviral therapy (ART). Since many antiretroviral agents have off target effects, and different classes target different components of the viral life cycle, we questioned whether different classes of ART might differentially affect the survival and persistence of productively HIV-infected CD4 T cells.MethodsIn vitro infections of primary CD4 T cells using clinical isolates of HIV-1 that were either protease inhibitor susceptible (HIV PI-S), or resistant (HIV PI-R) were treated with nothing, lopinavir, efavirenz or raltegravir. Cell viability, apoptosis, and the proportion of surviving cells that were P24 positive was assessed by flow cytometry.ResultsIn HIV PI-S infected primary cultures, all three antiretroviral agents decreased viral replication, and reduced the total number of cells that were undergoing apoptosis (P < 0.01) similarly. Similarly, in the HIV PI-R infected cultures, both efavirenz and raltegravir reduced viral replication and reduced apoptosis compared to untreated control (P < 0.01), while lopinavir did not, suggesting that HIV replication drives T cell apoptosis, which was confirmed by association by linear regression (P < 0.0001) . However since HIV protease has been suggested to directly induce apoptosis of infected CD4 T cells, and HIV PI are intrinsically antiapoptotic, we evaluated apoptosis in productively infected (HIV P24+) cells. More HIV p24 positive cells were apoptotic in the Efavirenz or raltegravir treated cultures than the lopinavir treated cultures (P = 0.0008 for HIV PI-R and P = 0.06 for the HIV PI-S), indicating that drug class impacts survival of productively infected CD4 T cells.ConclusionsInhibiting HIV replication with a PI, NNRTI or INSTI reduces total HIV-induced T cell apoptosis. However, blocking HIV replication with PI but not with NNRTI or INSTI promotes survival of productively HIV-infected cells. Thus, selection of antiretroviral agents may impact the success of HIV eradication strategies.Electronic supplementary materialThe online version of this article (doi:10.1186/2052-8426-2-1) contains supplementary material, which is available to authorized users.

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“…Xu et al [32] have reported that E 2 suppressed HSC proliferation and was paralleled by the inhibition of TGF-b1 and PDGF expression in CCl 4 -induced fibrosis in male and female rats. The induction of miR-29a and miR29b expression by E 2 was opposite to the effect of TGF-b1 [46].…”

Section: Micrornas and Gene Expression In Estrogen-dependent Functionsmentioning

confidence: 95%

“…Zhang et al [46] have reported the role of estrogen-induced miR-29 expression in CCl 4 -induced mouse liver injury. The levels of miR29a and miR-29b expression were significantly decreased in the livers of male, but not female mice, and the downregulation of miR-29a and miR-29b correlated with the early development of hepatic fibrosis.…”

Section: Micrornas and Gene Expression In Estrogen-dependent Functionsmentioning

confidence: 99%

“…The following mechanisms have been hypothesized to explain the antifibrogenic effect of estrogens [3,32,46]: (a) a hepatocellular membrane protection and radical scavenging action; (b) a modulation of HSC proliferation and collagen synthesis; (c) a modulation in the secretion of vasoactive substances, cytokines, and growth factors; and (d) regulation of transcription factors, microRNAs (miRNAs), and gene expression. In fact, all of these mechanisms interact and form a network, contributing toward the protective effect of estrogens, in which inhibition of HSCs and ECM secretion plays a central role and serves as a common pathway.…”

Section: Antifibrogenic Mechanisms Of Estrogensmentioning

confidence: 99%

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Estrogen derivatives

Zhang

Wu²

2013

European Journal of Gastroenterology & Hepatology

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Sex differences in the incidence of liver cirrhosis and portal hypertension have been reported by epidemiological studies. Previous studies have indicated that estrogen therapy improved hepatic fibrosis, inhibited the activation of hepatic stellate cells, and reduced portal pressure, whereas the administration of exogenous estrogens resulted in some potential risks, limiting their clinical use. However, the biological actions of estrogens are mediated by three subtypes of estrogen receptors (ERs): ERα, ERβ, and G-protein-coupled ER. These ER subtypes act in distinct ways and exert different biological effects that mediate genomic and nongenomic events, resulting in tissue-specific responses. In addition, active estrogen metabolites, with little or no affinity for ERs, could mediate the fibrosuppressive effect of estrogens through an ER-independent pathway. Taken together, such specific estrogen derivatives as ER selective agonists, or active estrogen metabolites, would provide novel therapeutic opportunities, stratifying this hormonal treatment, thereby reducing undesired side-effects in the treatment of liver cirrhosis and portal hypertension.

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Protective Role of Estrogen-induced miRNA-29 Expression in Carbon Tetrachloride-induced Mouse Liver Injury

Cited by 98 publications

References 47 publications

Downregulation of MicroRNA-30 Facilitates Podocyte Injury and Is Prevented by Glucocorticoids

Downregulation of MicroRNA-30 Facilitates Podocyte Injury and Is Prevented by Glucocorticoids

Choice of antiretroviral therapy differentially impacts survival of HIV-infected CD4 T cells

Estrogen derivatives

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