Activation of RhoA/ROCK regulates NF-κB signaling pathway in experimental diabetic nephropathy

Xie, Xi; Peng, Jing; Chang, Xiuting; Huang, Kaipeng; Huang, Juan; Wang, Shaogui; Shen, X. Y.; Liu, Peiqing; Huang, Heqing

doi:10.1016/j.mce.2013.01.007

Cited by 92 publications

(67 citation statements)

References 45 publications

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“…Previous studies showed that activation of RhoA/ROCK regulates NF-κB signaling pathway and RhoA/ROCK act upstream of p38 MAPK [22,23]. We performed western blot to explore whether miR-124-3p could affect these pathways.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-124-3p inhibits cell migration and invasion in bladder cancer cells by targeting ROCK1

Lin

et al. 2013

J Transl Med

109

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BackgroundIncreasing evidence has suggested that dysregulation of certain microRNAs (miRNAs) may contribute to human disease including carcinogenesis and tumor metastasis in human. miR-124-3p is down-regulated in various cancers, and modulates proliferation and aggressiveness of cancer cells. However, the roles of miR-124-3p in human bladder cancer are elusive. Thus, this study was conducted to investigate the biological functions and its molecular mechanisms of miR-124-3p in human bladder cancer cell lines, discussing whether it has a potential to be a therapeutic biomarker of bladder cancer.MethodsThree human bladder cancer cell lines and samples from ten patients with bladder cancer were analyzed for the expression of miR-124-3p by quantitative RT--PCR. Exogenetic overexpression of miR-124-3p was established by transfecting mimics into T24, UM-UC-3 and J82 cells, after that cell proliferation and cell cycle were assessed by MTT assay, flow cytometry and Colony-forming assay. Cell motility and invasion ability were evaluated by wound healing assay and transwell assay. Tissue microarray, and immunohistochemistry with antibodies against ROCK1, MMP2 and MMP9 was performed using the peroxidase and DAB methods. The target gene of miR-124-3p was determined by luciferase assays, quantitative RT--PCR and western blot. The regulation of epithelial-to-mesenchymal transition by miR-124-3p was analyzed by western blot.ResultsmiR-124-3p is frequently down-regulated in bladder cancer both in three bladder cancer cell lines, T24, UM-UC-3, J82 and clinical samples. Overexpression of miR-124-3p induced G1-phase arrest in T24, UM-UC-3 and J82 cell lines and suppressed cell growth in colony-forming assay. miR-124-3p significantly repressed the capability of migration and invasion of bladder cancer cells. In addition, ROCK1 was identified as a new target of miR-124-3p. ROCK1, MMP2, MMP9 were up-regulated in bladder cancer tissues. Furthermore, we demonstrated miR-124-3p could inhibit bladder cancer cell epithelial mesenchymal transfer, and regulated the expression of c-Met, MMP2, MMP9.ConclusionsmiR-124-3p can repress the migration and invasion of bladder cancer cells via regulating ROCK1. Our data indicate that miR-124-3p could be a tumor suppressor and may have a potential to be a diagnostics or predictive biomarker in bladder cancer.

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Section: Resultsmentioning

confidence: 99%

MicroRNA-124-3p inhibits cell migration and invasion in bladder cancer cells by targeting ROCK1

Lin

et al. 2013

J Transl Med

109

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“…Xie et al demonstrated that Rho/Rock modulation of NF-κB increased TGF-β1 and ICAM-1 expression, which resulted in increased fibronectin matrix protein synthesis in cultured human mesangial cells. Inhibition of ROCK with fasudil reduced the activation of Rho/Rock, along with reduced NF-κB translocation and fibronectin accumulation in rats with STZ-induced diabetes [123]. Fasudil treatment not only inhibited the ROCK activity but also reduces the process of epithelial-myofibroblast transdifferentiation or epithelial-mesenchymal transition of human renal HK-2 tubular epithelial cells subjected to HG ambience [124] (Figure 3).…”

Section: Small Gtpase and Ecmmentioning

confidence: 99%

Insights into the Mechanisms Involved in the Expression and Regulation of Extracellular Matrix Proteins in Diabetic Nephropathy

Hu¹,

Sun²,

Xiao³

et al. 2015

CMC

170

113

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Diabetic Nephropathy (DN) is believed to be a major microvascular complication of diabetes. The hallmark of DN includes deposition of Extracellular Matrix (ECM) proteins, such as, collagen, laminin and fibronectin in the mesangium and renal tubulo-interstitium of the glomerulus and basement membranes. Such an increased expression of ECM leads to glomerular and tubular basement membranes thickening and increase of mesangial matrix, ultimately resulting in glomerulosclerosis and tubulointerstitial fibrosis. The characteristic morphologic glomerular mesangial lesion has been described as Kimmelstiel–Wilson nodule, and the process at times is referred to as diabetic nodular glomerulosclerosis. Thus, the accumulation of ECM proteins plays a critical role in the development of DN. The relevant mechanism(s) involved in the increased ECM expression and their regulation in the kidney in diabetic state has been extensively investigated and documented in the literature. Nevertheless, there are certain other mechanisms that may yet be conclusively defined. Recent studies demonstrated that some of the new signaling pathways or molecules including, Notch, Wnt, mTOR, TLRs and small GTPase may play a pivotal role in the modulation of ECM regulation and expression in DN. Such modulation could be operational for instance Notch though Notch1/Jagged1 signaling, Wnt by Wnt/β-catenin pathway and mTOR via PI3-K/Akt/mTOR signaling pathways. All these pathways may be critical in the modulation of ECM expression and tubulo-interstitial fibrosis. In addition, TLRs, mainly the TLR2 and TLR4, by TLR2-dependent and TGF-β-dependent conduits, may modulate ECM expression and generate a fibrogenic response. Small GTPase like Rho, Ras and Rab family by targeting relevant genes may also influence the accumulation of ECM proteins and renal fibrosis in hyperglycemic states. This review summarizes the recent information about the role and mechanisms by which these molecules and signaling pathways regulate ECM synthesis and its expression in high glucose ambience in vitro and in vivo states. The understanding of such signaling pathways and the molecules that influence expression, secretion and amassing of ECM may aid in developing strategies for the amelioration of diabetic nephropathy.

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“…Mitogen-activated protein kinase (MAPK) family including P38, extracellular signal-regulated kinases (ERK), and c-Jun N-terminal kinases pathways are also found to cause DN [9–13]. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κ B), a key inflammatory pathway, recruits a variety of inflammatory cytokines involved in DN [14–16]. However, the molecular pathogenesis hidden behind is still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

The Role of MicroRNAs in Diabetic Nephropathy

Kong

Zhou

et al. 2014

Journal of Diabetes Research

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Diabetic nephropathy (DN), as one of the chronic complications of diabetes, is the major cause of end-stage renal disease. However, the pathogenesis of this disease is not fully understood. In recent years, research on microRNAs (miRNAs) has become a hotspot because of their critical role in regulating posttranscriptional levels of protein-coding genes that may serve as key pathogenic factors in diseases. Several miRNAs were found to participate in the pathogenesis of DN, while others showed renal protective effects. Therefore, targeting miRNAs that are involved in DN may have a good prospect in the treatment of the disease. The aim of this review is to summarize DN-related miRNAs and provide potential targets for diagnostic strategies and therapeutic intervention.

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Activation of RhoA/ROCK regulates NF-κB signaling pathway in experimental diabetic nephropathy

Cited by 92 publications

References 45 publications

MicroRNA-124-3p inhibits cell migration and invasion in bladder cancer cells by targeting ROCK1

MicroRNA-124-3p inhibits cell migration and invasion in bladder cancer cells by targeting ROCK1

Insights into the Mechanisms Involved in the Expression and Regulation of Extracellular Matrix Proteins in Diabetic Nephropathy

The Role of MicroRNAs in Diabetic Nephropathy

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