TGF-β1-Induced Epithelial-to-Mesenchymal Transition and Therapeutic Intervention in Diabetic Nephropathy

Hills, Claire E.; Squires, Paul E.

doi:10.1159/000256659

Cited by 177 publications

(162 citation statements)

References 133 publications

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“…In addition, its upregulation is a common characteristic of renal tubulointerstitial fibrosis in DN. 20 In this study, we first found that the mRNA and protein expression of FN, ColIV, and TGF-b1 was upregulated with HG stimulation, whereas NCTD could evidently inhibit their upregulation in a time-dependent manner. Because TGF-b1 can increase ECM protein synthesis, including ColIV and FN, we suggested that NCTD might downregulate FN and ColIV expression in HK-2 cells induced by HG through inhibition of TGF-b1 expression.…”

Section: Effects Of Nctd On Can/nfatc Signaling Pathway In Hk-2 Cellsmentioning

confidence: 74%

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Chen

Liu

et al. 2011

Laboratory Investigation

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Norcantharidin (NCTD) was shown in our previous studies to attenuate renal tubulointerstitial fibrosis in rat models with diabetic nephropathy (DN). The aim of this study was to determine the effects of NCTD on the expression of extracellular matrix (ECM) and TGF-b1 in HK-2 cells stimulated by high glucose and on calcineurin (CaN)/NFAT pathway. Whether or not the antifibrotic effect of NCTD on renal interstitium was dependent on its inhibition of CaN pathway was also investigated. Experimental concentrations of NCTD were verified by cytotoxic test and MTT assay. HK-2 cells were transfected with CaN small interference RNA (siRNA). The mRNA and protein expressions of FN, ColIV, TGF-b1, and CaN in HK-2 cells were detected by real-time PCR and western blot. The CaN/NFAT pathway was examined by indirect immunofluorescence and western blot. Our study revealed that NCTD concentrations over 5 mg/l had overt cytotoxicity on HK-2 cells. Meanwhile, both 2.5 and 5 mg/l NCTD inhibited HK-2 cell proliferation (Po0.05). NCTD inhibited the upregulation of FN, ColIV, and TGF-b1 of HK-2 cells stimulated by high glucose (Po0.05), and also significantly downregulated the expression of CaN mRNA and protein in HK-2 cells (Po0.05). In addition, not only was the nuclear translocation of NFATc inhibited, but its protein level in the nucleus was also reduced. Following CaN siRNA transfection, CaN mRNA and protein expression were significantly decreased. In contrast, the protein levels of FN, ColIV, and TGF-b1 increased in HK-2 cells stimulated by high glucose (Po0.05). However, NCTD treatment downregulated their expression. These results indicated that NCTD could decrease the expression of ECM and TGF-b1 in HK-2 cells stimulated by high glucose, downregulate CaN expression, and block the CaN/NFAT signaling pathway. However, the effect of NCTD on inhibition of the expression of ECM and TGF-b1 was not associated with its inhibition of the CaN/NFAT pathway.

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Section: Effects Of Nctd On Can/nfatc Signaling Pathway In Hk-2 Cellsmentioning

confidence: 74%

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Chen

Liu

et al. 2011

Laboratory Investigation

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“…28,29 Epithelial-to-mesenchymal transition, a process by which differentiated epithelial cells undergo a phenotypic conversion that gives rise to the matrix-producing fibroblasts and myofibroblasts, is increasingly recognized as an integral part of tissue fibrogenesis after injury. Emerging evidence suggests that TGF-b initiates the transition of renal tubular epithelial cells to myofibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of a combination of Rho-kinase inhibitor and ACE inhibitor on tubulointerstitial fibrosis induced by unilateral ureteral obstruction

et al. 2010

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We and others recently reported that long-term Rho-kinase inhibition has renoprotective effects. This study was designed to compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (imidapril), a Rho-kinase inhibitor (fasudil) and a combination of them both on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). We also attempted to elucidate the mechanism involved. Imidapril (50 mg l -1 ), fasudil (1 g l -1 ) or a combination of them both was given in drinking water to mice, and their effects were compared on renal interstitial fibrosis induced by UUO. We assessed histological findings, monocyte/macrophage infiltration, myofibroblast differentiation, oxidative stress and the expression of various mRNA in the kidney by UUO. Eleven days after UUO, wild-type kidney was characterized by increased fibrotic area, dihydroethidium (DHE)-positive area, a-smooth muscle actin (SMA)-positive area, F4/80-positive area and the increased expression of various mRNA. Fasudil and imidapril similarly improved fibrotic area (À23%, À15%), DHE-positive area (À13%, À11%), a-SMA-positive area (À22%, À15%), F4/80-positive area (À42%, À34%) and the expression of various mRNA, most of which were significant (Po0.05). The combination of imidapril and fasudil further improved fibrotic area (À52%), DHE-positive area (À26%), a-SMApositive area (À33%), F4/80-positive area (À62%) and the expression of various mRNA (all Po0.05 vs. monotherapy). Compared with either agent alone, the combination of an ACE inhibitor and a Rho-kinase inhibitor was more effective for the prevention of renal interstitial fibrosis because of the inhibition of transforming growth factor-b/collagen, monocyte/macrophage infiltration, myofibroblast differentiation, inflammation and the oxidative stress pathway.

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“…Understanding those mediating signals which regulate deposition of fibrotic material in the interstitium is critical to future identification and development of site specific therapeutics which may alleviate this damage. Central to TIF is tubular epithelial-tomesenchymal transition (EMT), or the transdifferentiation of tubular epithelial cells into myofibroblasts [9][10]. In DN, EMT occurs as cells attempt to evade apoptosis as a consequence of exposure to pathophysiological stimuli [11][12].…”

Section: Introductionmentioning

confidence: 99%

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Hills

Squires

2011

Cytokine & Growth Factor Reviews

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Transforming Growth Factor-beta (TGF-β) is a pro-sclerotic cytokine widely associated with the development of fibrosis in diabetic nephropathy. Central to the underlying pathology of tubulointerstitial fibrosis is epithelial-to-mesenchymal transition (EMT), or the trans-differentiation of tubular epithelial cells into myofibroblasts. This process is accompanied by a number of key morphological and phenotypic changes culminating in detachment of cells from the tubular basement membrane and migration into the interstitium. Ultimately these cells reside as activated myofibroblasts and further exacerbate the state of fibrosis. A large body of evidence supports a role for TGF-β and downstream Smad signaling in the development and progression of renal fibrosis. Here we discuss a role for TGF-β as the principle effector in the development of renal fibrosis in diabetic nephropathy, focusing on the role of the TGF-β1 isoform and its downstream signaling intermediates, the Smad proteins. Specifically we review evidence for TGF-β1 induced EMT in both the proximal and distal regions of the nephron and describe potential therapeutic strategies that may target TGF-β1 activity.

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TGF-β1-Induced Epithelial-to-Mesenchymal Transition and Therapeutic Intervention in Diabetic Nephropathy

Cited by 177 publications

References 133 publications

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Beneficial effects of a combination of Rho-kinase inhibitor and ACE inhibitor on tubulointerstitial fibrosis induced by unilateral ureteral obstruction

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

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