Advanced Glycation End Products Activate the mi<scp>RNA</scp>/RhoA/<scp>ROCK</scp>2 Pathway in Endothelial Cells

Wu, Xiaodan; Li, Weilin; Zeng, Kai; Lei, Hongyi; Zhang, Qingguo; Zhou, Shuqin; Xu, Shiyuan

doi:10.1111/micc.12104

Cited by 28 publications

(23 citation statements)

References 43 publications

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“…Based on these findings, it is not surprising that overexpression of Smad7 significantly mitigated renal fibrosis in a rat unilateral ureteral obstruction model [32]. Conversely, Smad7-deficient diabetic mice exhibited more severe renal fibrosis, albuminuria, and inflammation compared with those with a normal genotype [27]. e results of these studies were consistent with our observation of downregulated Smad7 expression in rat kidney tissues exposed to a hyperglycemic environment.…”

Section: Discussionsupporting

confidence: 86%

“…A series of recent studies have considerably furthered our understanding of the pathogenic role of Smad7 in DN [27][28][29]. e transforming growth factor-β (TGF-β)-Smad signaling pathway has been shown to be a key regulator of Evidence-Based Complementary and Alternative Medicine ECM homeostasis, a process closely associated with the development of the disease.…”

Section: Discussionmentioning

confidence: 99%

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MiR‐92b‐3p is Induced by Advanced Glycation End Products and Involved in the Pathogenesis of Diabetic Nephropathy

Wang

Geng

Sun

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Purpose. The current study aims to examine the effects of advanced glycation end products (AGEs) on the microRNA (miRNA) expression profile in the kidney tissues of rats. Methods. Wistar rats were randomly divided into three equal experiment groups: the AGE group, the RSA group, and the control group. The rats in the AGE group and the RSA group were administered with advanced glycation end products (AGEs) and rat serum albumin (RSA) via the tail vein, respectively, whereas the control group received PBS. Total RNA was prepared from the rat kidney tissues, and the miRNA expression profiles in different experiment groups were compared by microarray analysis. The expression levels of selected differential miRNAs were verified by RT-qPCR. Target gene prediction was conducted using algorithms such as TargetScan, miRanda, and PICTar. Functional analysis was performed to determine the putative biological roles of the validated miRNAs. Results. The microarray study revealed 451 upregulated and 320 downregulated miRNAs in the AGE group compared with the RSA group (p<0.05). Seven miRNAs, including miR-21-5p, miR-92b-3p, miR-140-3p, miR-196a-5p, miR-181b-5p, miR-186-5p, and miR-192-5p, were screened and verified using RT-qPCR, of which, the change of miR-92b-3p was the most obvious according to the miRNA expression different multiple and p value. Furthermore, the expression trend of miR-92b-3p measured by RT-qPCR was shown to be consistent with the microarray results. Bioinformatics analysis and luciferase reporter assay identified Smad7 was a direct target of miR-92b-3p. Both immunohistochemical and western blotting showed that Smad7 expression was significantly suppressed in the kidney tissues from the AGE group compared with the control and RSA groups. Conclusion. The results of the current study suggested that miR-92b-3p could mediate AGE-induced development of renal abnormalities through targeting Smad7 in rats with DN.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

MiR‐92b‐3p is Induced by Advanced Glycation End Products and Involved in the Pathogenesis of Diabetic Nephropathy

Wang

Geng

Sun

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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“…Rho associated proteins are involved in an abundant of cell processes, containing proliferation, cytoskeletal actin remodeling, differentiation, and the generation of ROS [21]. ROCK2 is one of isoforms of ROCK and the down-stream effector of RhoA which enhances cell motility via inhibition of myosin phosphatase [20,22].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

MicroRNA-141 Inhibits the Proliferation of Penile Cavernous Smooth Muscle Cells Associated with Down-Regulation of the Rhoa/Rho Kinase Signaling Pathway

Zhang¹,

Jia²,

Ji³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The role of the RhoA/Rho kinase signaling pathway in diabetes mellitus-induced erectile dysfunction has been partially understood. Methods: In the present study, we explored the changes of the RhoA/Rho associated kinase (ROCK) signaling pathway in diabetic erectile dysfunction in vivo and the effects of microRNA-141 on the RhoA/ROCK signaling pathway in vitro. Results: The mRNA and protein expressions of RhoA and ROCK2 were significantly increased while the expression of microRNA-141 was decreased in the penile cavernous smooth muscle cells of rats with diabetic erectile dysfunction. Moreover, increased expression of microRNA-141, decreased expressions of RhoA and ROCK2 (mRNA and protein), accelerated cell proliferation rate and reduced cell apoptosis were found in the microRNA-141 mimics group and the siRNA-Rho group. The microRNA-141 expression in the microRNA-141 inhibitors + siRNA-Rho group was significantly decreased. microRNA-141 specifically bound to Rho-3’-UTR and down-regulated the expression of Rho gene at the post transcriptional level. Conclusion: Decreased expression of miR-141 is associated with up-regulation of RhoA and ROCK2 in the RhoA/ROCK signaling pathway in rats with diabetic erectile dysfunction. miR-141 inhibits the growth of penile cavernous smooth muscle cells associated with down-regulation of the RhoA/ROCK signaling pathway in vitro.

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“…These results suggested that the histone methylation activity may have vital roles in SMYD3-mediated transactivation of miR-200c-3p. (60,61). As the results of the present study demonstrated the overexpression of SMYD3 directly transactivates miR-200c-3p, whether SMYD3 and miR-200c-3p supports or opposes each others' effects on the transcription of MYL9 and CYR61, two MRTF-A-dependent migration-related genes, was investigated.…”

Section: Histone Methylation Activity Is Essential In the Smyd3-mediamentioning

confidence: 73%

Effect of SMYD3 on the microRNA expression profile of MCF-7 breast cancer cells

et al. 2017

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Abstract. SET and MYND domain containing 3 (SMYD3) is a histone methyltransferase (HMT) and transcription factor, which serves important roles in carcinogenesis. Numerous downstream target genes of SMYD3 have been identified in previous studies. However, the downstream microRNA (miRNA) s regulated by SMYD3 are yet to be elucidated. In the present study, the results of miRNA microarray demonstrated that 30 miRNA expression profiles were upregulated, whilst 24 miRNAs were downregulated by >2.0-fold in the SMYD3-overexpressed MCF-7 breast cancer cells. The HMT activity was demonstrated to be essential for SMYD3-mediated transactivation of miR-200c-3p and the overexpression of miR-200c-3p inhibited the transactivation effects of SMYD3 on myocardin-related transcription factor-A-dependent migration-associated genes. To our best knowledge, the current study is the first to report on the transcriptional regulation of SMYD3 on miRNAs, and miR-200c may be a downstream negative regulator of the SMYD3-mediated pathway in the migration of breast cancer cells. These results may provide a novel theoretical basis to understand the mechanisms underlying the initiation, progression, diagnosis, prevention and therapy of breast cancer. IntroductionSET and MYND domain containing 3 (SMYD3) is a novel histone methyltransferase gene identified in hepatoma and colon carcinoma cells by Hamamoto et al (1). SMYD3 is located on human chromosome 1 and encodes two protein isoforms that are composed of 428 and 369 amino acids. Previous studies have demonstrated that SMYD3 is frequently overexpressed in numerous types of cancer cells, including hepatic, colon, gastric and cervical carcinoma, and breast cancer (2-4), whilst the expression levels were lower in the corresponding normal tissue. A number of previous studies have demonstrated that SMYD3 has vital roles in the process of tumor development via its functions as a histone methylation enzyme and a transcription factor (5,6). SMYD3 modifies chromatin structure by catalyzing the methylation of histone H3 at lysine 4 (H3K4), H4K20 and H4K5 (5,6). Also, SMYD3 regulates the transcription of target genes via associating with RNA polymerase II or HELZ RNA helicase and binding at the motif CCCTCC or GGAGGG in the promoter (1).MicroRNAs (miRNAs) are small, non-coding, endogenous RNA molecules of 18-22 nucleotides that were first identified in Caenorhabditis elegans. miRNAs suppress gene expression by binding the targeted mRNA transcripts, which causes translational repression or mRNA degradation. Previous studies demonstrated that miRNAs serve important roles in tumorigenesis through the regulation of genes involved in cancer development and maintenance (7,8).A number of studies have identified that histone methylation and miRNAs are essential in the initiation and progression of cancer (7-9). However, the association between SMYD3 and miRNAs is yet to be elucidated. To investigate this further, the current study analyzed the global regulatory effects of SMYD3 on miRNAs in breast cancer cells usi...

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Advanced Glycation End Products Activate the miRNA/RhoA/ROCK2 Pathway in Endothelial Cells

Abstract: miR-200b and miR-200c are suppressed in AGE-induced endothelial cell injury, resulting in unregulated RhoA/ROCK2 signaling. Further studies are necessary to evaluate the therapeutic value of targeting miRNAs or their target genes for treatment of vascular diseases.

Cited by 28 publications

References 43 publications

MiR‐92b‐3p is Induced by Advanced Glycation End Products and Involved in the Pathogenesis of Diabetic Nephropathy

MiR‐92b‐3p is Induced by Advanced Glycation End Products and Involved in the Pathogenesis of Diabetic Nephropathy

MicroRNA-141 Inhibits the Proliferation of Penile Cavernous Smooth Muscle Cells Associated with Down-Regulation of the Rhoa/Rho Kinase Signaling Pathway

Effect of SMYD3 on the microRNA expression profile of MCF-7 breast cancer cells

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