New insights into the mechanism of notch signalling in fibrosis.

Laboratoire d'immunologie, EA 1833, Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), France.
The Open Rheumatology Journal 01/2012; 6:96-102. DOI: 10.2174/1874312901206010096
Source: PubMed

ABSTRACT The Notch pathway is an evolutionary conserved signalling mechanism that regulates cellular fate and development in various types of cells. The full spectrum of Notch effects has been well studied over the last decade in the fields of development and embryogenesis. But only recently several studies emphasized the involvement of the Notch signalling pathway in fibrosis. This review summarizes the structure and activation of the Notch family members, and focuses on recent findings regarding the role of Notch in organ fibrogenesis, in humans and in animal models.

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    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, 250μg/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.
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    ABSTRACT: The effects of the Notch signaling pathway in fibroproliferative skin diseases have not been fully elucidated.
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