Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGF-β2 in human retinal pigment epithelial cells

Itoh, Yuji; Kimoto, Katsuhiko; Imaizumi, Masamoto; Nakatsuka, Kazuo

doi:10.1016/j.exer.2006.10.017

Cited by 55 publications

(43 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…29,46 Our data also supported that laminin production is dependent on Smad4. The feeble effect of knockdown Smad4 on collagen I may be due to other intracellular signaling pathways that regulate collagen I, requiring further study.…”

Section: Discussionsupporting

confidence: 77%

MicroRNA-483-3p Inhibits Extracellular Matrix Production by Targeting Smad4 in Human Trabecular Meshwork Cells

Shen

Han

Huang

et al. 2015

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

PURPOSE. This study investigated the effects of microRNA-483-3p (miR-483-3p) on extracellular matrix (ECM) production, and clarified the regulatory mechanism of microRNA-483-3p in human trabecular meshwork cells (HTMCs) under oxidative stress. METHODS.The expression levels of ECM (fibronectin, laminin, collagen I) in HTMCs under oxidative stress were measured by Western blot. Changes of miR-483-3p expression in HTMCs were evaluated by quantitative polymerase chain reaction (qPCR). After using lentivirus stably expressing pri-miR-483, the effects of miR-483-3p on the ECM were assessed by qPCR and Western blot. Smad4, the potential target of miR-483-3p according to mRNA target-predicting algorithms, was confirmed by luciferase assay and Western blot. Furthermore, the effects of Smad4 knockdown on ECM expression were investigated by qPCR and Western blot.RESULTS. The mRNA and protein levels of ECM (fibronectin, laminin, collagen I) were upregulated in HTMCs induced by oxidative stress. The expression level of miR-483-3p decreased in HTMCs under oxidative stress, and the ectopic expression of miR-483-3p decreased the levels of ECM. In addition, miR-483-3p targeted Smad4 through two binding sites, resulting in a decrease of Smad4 expression. Furthermore, knockdown of Smad4 reduced the levels of ECM in HTMCs.CONCLUSIONS. MicroRNA-483-3p has an inhibitory effect on ECM production in HTMCs through downregulating Smad4, which indicates that miR-483-3p may serve as a potential therapeutic target in glaucoma.

show abstract

Section: Discussionsupporting

confidence: 77%

MicroRNA-483-3p Inhibits Extracellular Matrix Production by Targeting Smad4 in Human Trabecular Meshwork Cells

Shen

Han

Huang

et al. 2015

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

show abstract

“…The converse was not true, as inhibition of ROCK or RhoA had no effect on CDH11-induced phosphorylation of SMAD2 or SMAD3. The crosstalk between the two pathways has been previously reported especially in the context of the role of TGF-β in ECM production (Itoh et al, 2007;Zhu et al, 2013) but our study demonstrates that such crosstalk also exists in the context of CDH11-mediated intercellular adhesion. Currently, the nature of the effector(s) mediating this inter-connection remains unknown.…”

Section: Discussionmentioning

confidence: 53%

Cadherin-11 is a novel regulator of extracellular matrix synthesis and tissue mechanics

Row

Liu

Alimperti

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

We discovered that Cadherin-11 (CDH11) regulates collagen and elastin synthesis, both affecting the mechanical properties and contractile function of animal tissues. Using a Cdh11-null mouse model, we observed a significant reduction in the mechanical properties [Youngs' modulus and ultimate tensile strength (UTS)] of Cdh11 −/− as compared to wild-type (WT) mouse tissues, such as the aorta, bladder and skin. The deterioration of mechanical properties (Youngs' modulus and UTS) was accompanied by reduced collagen and elastin content in Cdh11 −/− mouse tissues as well as in cells in culture. Similarly, knocking down CDH11 abolished collagen and elastin synthesis in human cells, and consequently reduced their ability to generate force. Conversely, engagement of CDH11 through homophilic interactions, led to swift activation of the TGF-β and ROCK pathways as evidenced by phosphorylation of downstream effectors. Subsequently, activation of the key transcription factors, MRTF-A (also known as MKL1) and MYOCD led to significant upregulation of collagen and elastin genes. Taken together, our results demonstrate a novel role of adherens junctions in regulating extracellular matrix (ECM) synthesis with implications for many important biological processes, including maintenance of tissue integrity, wound healing and tissue regeneration.

show abstract

“…In addition, RhoA activation generally is observed transiently, and returns spontaneously to basal levels. 33,34 Thus, the instability of RhoA activity might be another factor related to this difference. Even after transient activation of RhoA, the prolonged effects of activation of ROCK and MLC could cause changes in aqueous outflow.…”

Section: Discussionmentioning

confidence: 99%

Involvement of RhoA/Rho-Associated Kinase Signal Transduction Pathway in Dexamethasone-Induced Alterations in Aqueous Outflow

Fujimoto

Inoue

Kameda

et al. 2012

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

PURPOSE. We investigated the involvement of the RhoA/Rho kinase (ROCK) signal transduction pathway in dexamethasone (DEX)-induced changes in aqueous outflow.METHODS. Using trabecular meshwork (TM) and Schlemm's canal endothelial (SCE) cells, RhoA activation was evaluated with a pull-down assay and myosin light chain phosphorylation was evaluated by Western blot analysis. Outflow facility was measured in perfused porcine anterior segment organ cultures treated with DEX and/or Y-27632, a selective ROCK inhibitor. The barrier function of the cultured cells on a micropore filter was evaluated by measuring the transendothelial electrical resistance. Collagen, fibronectin, and integrin mRNA expression levels were evaluated by quantitative realtime RT-PCR. RESULTS.Relative RhoA activities increased following stimulation with 100 nM DEX in TM and SCE cells. Perfusion with DEX decreased outflow facility by 31.9 6 14.3% compared to controls at 24 hours, but not by 50 lM Y-27632 in addition to DEX. The transendothelial electrical resistance of the SCE cell monolayer was increased by 48.6 6 6.4% and 5.3 6 5.0% following DEX treatments without and with 10 lM Y-27632, respectively, compared to controls. In TM cells, the mRNA expressions of COL4A1 and fibronectin were increased significantly by DEX treatment, but combined treatment with Y-27632 and DEX significantly inhibited the increase in COL4A1and fibronectin expression.CONCLUSIONS. Activation of the Rho/ROCK pathway in SCE cells contributes to the mechanism of DEX-induced changes in aqueous outflow. (Invest Ophthalmol Vis Sci. 2012;53:7097-7108) DOI:10.1167/iovs.12-9989 S teroid-induced ocular hypertension is an important clinical problem related to the use of glucocorticoid therapy for many types of disorders. Already in 1963, Armaly reported that the widely used glucocorticoid dexamethasone (DEX) induces changes in intraocular pressure (IOP) and fluid dynamics in normal eyes, and that DEX-induced IOP elevation is observed more frequently in the patients with glaucoma. 1-3 IOP levels often are quite high in patients with steroid-induced ocular hypertension, and prolonged IOP elevation sometimes results in the loss of visual function. Topical administration of triamcinolone acetonide (TA), a synthetic corticosteroid, is considered a useful therapeutic modality for the management of intraocular inflammatory and/or proliferative diseases. The increasing number of patients treated with TA by intravitreous and/or sub-Tenon injections, however, has attracted the attention of ophthalmologists because of the potential risk of steroid-induced ocular hypertension. 4,5The mechanisms underlying steroid-induced ocular hypertension are associated with abnormal changes in the conventional outflow pathway caused by steroid administration. Some researchers attribute the decreased outflow to an accumulation of extracellular matrix (ECM) components, such as glycosaminoglycans, collagens, fibronectin, and elastin. [6][7][8][9] Others have proposed that the decreased outflow is due to decrea...

show abstract

Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGF-β2 in human retinal pigment epithelial cells

Cited by 55 publications

References 40 publications

MicroRNA-483-3p Inhibits Extracellular Matrix Production by Targeting Smad4 in Human Trabecular Meshwork Cells

MicroRNA-483-3p Inhibits Extracellular Matrix Production by Targeting Smad4 in Human Trabecular Meshwork Cells

Cadherin-11 is a novel regulator of extracellular matrix synthesis and tissue mechanics

Involvement of RhoA/Rho-Associated Kinase Signal Transduction Pathway in Dexamethasone-Induced Alterations in Aqueous Outflow

Contact Info

Product

Resources

About