title: The Notch γ-secretase inhibitor ameliorates kidney fibrosis via inhibition of TGF-β/Smad2/3 signaling pathway activation.
abstract: 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/100g/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.
authors.affiliation: Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Peng
authors.affiliation: Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of Physiology and Pathophysiology, Capital Medical University, Beijing, China.
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
authors.affiliation: Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China. Electronic address: jdu@bcm.edu.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003984:Dibenzazepines / Q000494:pharmacology*; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D003984:Dibenzazepines; D051880:Receptors, Notch; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D053829:Amyloid Precursor Protein Secretases; C527817:dibenzazepine
keywords: Epithelial-to-mesenchymal transition; Fibroblast; Kidney fibrosis; Notch; TGF-β