کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8323019 | 1539889 | 2014 | 7 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
The Notch γ-secretase inhibitor ameliorates kidney fibrosis via inhibition of TGF-β/Smad2/3 signaling pathway activation
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کلمات کلیدی
intracellular domain of NotchUUOICNdibenzazepineDBZSMADECMHES-1NICDTECsTGF-βsmall mother against decapentaplegicepithelial mesenchymal transition - انتقال مزانشیمی epithelialUnilateral ureteral obstruction - انسداد مجاری مدفوع یک طرفهBrdU - بروموداکسی اوریدینbromodeoxyuridine - برومودسوویریدینEMT - تکنسین فوریتهای پزشکیNotch intracellular domain - دامنه درون سلولی Notchtubular epithelial cells - سلولهای اپیتلیال لوله ایFibroblast - فیبروبلاستKidney fibrosis - فیبروز کلیهExtracellular matrix - ماتریکس خارج سلولیNotch - نچepithelial-to-mesenchymal transition - گذار اپیتلیال به مزانشیمال
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Kidney fibrosis is a common feature of chronic kidney disease (CKD). A recent study suggests that abnormal Notch signaling activation contributes to the development of renal fibrosis. However, the molecular mechanism that regulates this process remains unexplored. Unilateral ureteral obstruction (UUO) or sham-operated C57BL6 mice (aged 10 weeks) were randomly assigned to receive dibenzazepine (DBZ, 250 μg/100 g/d) or vehicle for 7 days. Histologic examinations were performed on the kidneys using Masson's trichrome staining and immunohistochemistry. Real-time PCR and western blot analysis were used for detection of mRNA expression and protein phosphorylation. The expression of Notch 1, 3, and 4, Notch intracellular domain (NICD), and its target genes Hes1 and HeyL were upregulated in UUO mice, while the increase in NICD protein was significantly attenuated by DBZ. After 7 days, the severity of renal fibrosis and expression of fibrotic markers, including collagen 1α1/3α1, fibronectin, and α-smooth muscle actin, were markedly increased in UUO compared with sham mice. In contrast, administration of DBZ markedly attenuated these effects. Furthermore, DBZ significantly inhibited UUO-induced expression of transforming growth factor (TGF)-β, phosphorylated Smad 2, and Smad 3. Mechanistically, Notch signaling activation in tubular epithelial cells enhanced fibroblast proliferation and activation in a coculture experiment. Our study provides evidence that Notch signaling is implicated in renal fibrogenesis. The Notch inhibitor DBZ can ameliorate this process via inhibition of the TGF-β/Smad2/3 signaling pathway, and might be a novel drug for preventing chronic kidney disease.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: The International Journal of Biochemistry & Cell Biology - Volume 55, October 2014, Pages 65-71
Journal: The International Journal of Biochemistry & Cell Biology - Volume 55, October 2014, Pages 65-71
نویسندگان
Zhicheng Xiao, Jing Zhang, Xiaogang Peng, Yanjun Dong, Lixin Jia, Huihua Li, Jie Du,