Disease relevance of Smad7

• Additionally, bile duct ligation (BDL)-induced fibrosis is ameliorated by introducing adenoviruses expressing Smad7 with down-regulated collagen and alpha-smooth muscle actin (alpha-SMA) expression [1].
• Hypertension of equivalent magnitude (190 to 200 mmHg) developed in both Smad7- and empty vector-treated rats [2].
• Preincubation of the cells with an NF-kappa B pathway inhibitor N-tosyl-l-phenylalanine chloromethyl ketone or infection of the cells with an adenovirus expressing an I kappa B super-repressor (Ad5I kappa B) abolished the NE-induced Smad7 expression [3].
• Localization of Smad6 and Smad7 in the rat kidney and their regulated expression in the anti-Thy-1 nephritis [4].
• The ability of Smad7 to inhibit renal inflammation indicates that ultrasound-microbubble-mediated Smad7 gene therapy may represents a new therapeutic strategy for glomerulonephritis [5].
• In rats transfected with a Smad7 transgene using an ultrasound-microbubble-mediated system, peritoneal fibrosis was attenuated, peritoneal function was improved, and Smad2/3 activation was inhibited [6].

High impact information on Smad7

• Such a beneficial effect was also observed when Smad7 was expressed in animals with established fibrosis [7].
• Animals received injections of an adenovirus carrying Smad7 cDNA into the portal vein during surgery and via the tail vein at later stages [7].
• Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats [7].
• RESULTS: Smad7-overexpressing BDL rats displayed reduced collagen and alpha-SMA expression and reduced hydroxyproline content in the liver, when compared with animals administered AdLacZ [7].
• Smad7 did not decrease expression of alpha-SMA, but immunofluorescent staining with anti alpha-SMA antibodies displayed destruction of the fibrillar organization of the actin cytoskeleton [7].

Chemical compound and disease context of Smad7

• To investigate a negative regulatory role of Smad7 in renal fibrosis, the Smad 7 gene was stably transfected and its expression was tightly controlled by doxycycline into NRK52E cells [8].
• RESULTS: Compared with the hepatic fibrosis models, the levels of TGF-beta1, TRII mRNA and the expression Smad3 significantly decreased in the two treated groups, and the expression of Smad7 was significantly increased in the liver of rats treated with perindopril or valsartan (P < 0.05 or P < 0.01) [9].

Biological context of Smad7

• Smad7 transgene expression within the kidney was tightly controlled by the addition of doxycycline in the daily drinking water [2].
• Smad7 mediates transforming growth factor-beta-induced apoptosis in mesangial cells [10].
• Overexpression of Smad7 induced DNA fragmentation and significant increases in cell death ELISA and CPP32/caspase-3 assay [10].
• TGF-beta(1) (10 ng/ml) was found to increase cytosolic Smad 7 expression in primary adult rat fibroblasts and induce rapid nuclear export of exogenous Smad 7 in COS-7 cells [11].
• Genomic locus and promoter region of rat Smad7, an important antagonist of TGFbeta signaling [12].

Anatomical context of Smad7

• Ectopic expression of Smad7 inhibits transforming growth factor-beta responses in vascular smooth muscle cells [13].
• Smad7 inhibits fibrotic effect of TGF-Beta on renal tubular epithelial cells by blocking Smad2 activation [8].
• Inhibitory Smads, Smad6 and Smad7, were strongly expressed in the zone of cartilage that contained mature chondrocytes [14].
• Here, we examined the expression of Smad1 to Smad7 proteins during endochondral ossification of epiphyseal plate of growing rats using immunohistochemical techniques [14].
• Overexpression of Smad7 did not affect nuclear factor-kappaB activity in mesangial cells [10].

Associations of Smad7 with chemical compounds

• Groups of six rats were subjected to 5/6 nephrectomy and received renal arterial injection of a doxycycline-regulated Smad7 gene or control empty vector using an ultrasound-microbubble-mediated system [2].
• Furthermore, Ang II rapidly induced inhibitory Smad7 mRNA expression [15].
• Angiotensin II promotes the proliferation of activated pancreatic stellate cells by Smad7 induction through a protein kinase C pathway [15].
• Smad7 is induced by norepinephrine and protects rat hepatocytes from activin A-induced growth inhibition [3].
• This initiation of transcription is dependent on functional tyrosine kinase receptors and can be blocked by Smad7 [16].

Enzymatic interactions of Smad7

• The different regulation of inhibitory Smad-7 was detected in irradiated and irradiated plus anti-TGFbeta1 treated animals by semiquantitative RT-PCR and the nucleocytoplasmic shuttling of phosphorylated Smad-3 was shown by isolation of nuclear proteins and Western blot analysis [17].

Regulatory relationships of Smad7

• Conversely, Id1 overexpression in HSCs enhanced cell activation and circumvented Smad7-dependent inhibition of transdifferentiation [1].
• Interestingly, Smad6 and Smad7 expression was also up-regulated in cells with increased Smad2 activation [18].
• Smad6 and Smad7 inhibit signaling by members of the TGF-beta superfamily [14].
• Furthermore, we report that the overexpression of Smad 7 mRNA could induce an activation of c-Jun N-terminal kinase, because of the observed c-Jun overexpression, activation, and nuclear translocation leading to an increase in the transcription of the proapoptotic factor Fas-L [19].
• These results indicated that ERK activation negatively regulated Smad7 transcription possibly by inhibiting translocation of Smad complex to nuclei [20].

Other interactions of Smad7

• Overexpression of the TGF-beta antagonist Smad7 inhibits transdifferentiation and arrests HSCs in a quiescent stage [1].
• Ectopic Smad7 expression in HSCs strongly reduced Id1 mRNA and protein expression [1].
• IFN-gamma treatment of MEC activates and relocalizes signal transducer and activator of transcription-1 (STAT-1) to induce an inhibitor SMAD, SMAD7 [21].
• The mechanisms might be associated with their effects of down-regulating TGF-beta1, TRII mRNA and Smad3, and up-regulating Smad7 [22].
• We investigated expressions and localizations of TGR1, Smad2, Smad4, and Smad7 by using semi-quantitative RT-PCR and immunohistochemistry in preneoplastic lesions during rat chemical hepatocarcinogenesis induced by Solt and Farber's method [23].

Analytical, diagnostic and therapeutic context of Smad7

• The ability of Smad7 to block Smad2/3 activation and attenuate renal and vascular sclerosis demonstrates that ultrasound-mediated Smad7 gene therapy may be a useful therapeutic strategy for the prevention of renal fibrosis in association with hypertension [2].
• METHODS: Primary cultured rat mesangial cells were transfected with Smad7-promoter-luciferase-plasmid by electroporation [10].
• The expressions of TGF-beta1, Smad3 and Smad7 in liver tissues were evaluated by immunohistochemistry [22].
• RT-PCR showed that TGF-beta1 mRNA expression was reduced by tetrandrine treatments from 56.56% to 87.90% in comparison with the control, while Smad 7 mRNA was increased 1.4-4.8 times [24].
• The up-regulation of Smad 7 protein by tetrandrine (1 mg/L) was confirmed by Western blotting as well [24].

References