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The deposition of N otch1 in hepatitis B virus‐associated nephropathy and its role in hepatitis B virus X protein‐induced epithelial–mesenchymal transdifferentiation and immunity disorder in renal tubular epithelial cells
Author(s) -
Wang X.,
Zhou Y.,
Zhu N.,
Wang L.,
Gu L.J.,
Yuan W.J.
Publication year - 2014
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/jvh.12244
Subject(s) - hbx , transdifferentiation , cancer research , hepatitis b virus , immune system , epithelial–mesenchymal transition , biology , downregulation and upregulation , immunology , virus , microbiology and biotechnology , stem cell , biochemistry , gene
Summary Notch1 plays an important role in the regulation of immune responses and epithelial–mesenchymal transdifferentiation ( EMT ). Previous studies have observed inflammatory cell infiltration and tubulointerstitial fibrosis in the renal biopsies from patients with HBV ‐associated glomerulonephritis ( HBV ‐ GN ). We hypothesized that N otch1 may be involved in the progression of HBV ‐ GN . In this study, we evaluated the distribution of N otch1 in patients with HBV ‐ GN . Our results showed that N otch1 was mainly distributed in renal tubules and the interstitial area, and the expression levels of N otch1 had a positive correlation with the renal tubular pathology. In this respect, we used human proximal tubular epithelial cells ( HK ‐2) as target cells, which were transiently transfected with the hepatitis B virus X ( HB x) gene using a eukaryotic vector. HB x expression resulted in significantly increased detection of Notch1, alpha‐smooth muscle actin (α‐ SMA ), major histocompatibility complex‐ II ( MHC ‐II), CD 40 and interleukin‐4 ( IL ‐4). At the same time, E‐cadherin and interferon‐γ ( IFN ‐γ) expression levels were significantly inhibited. These HB x‐induced phenotypes were exacerbated by upregulation of N otch1. K nock‐down of N otch1 by specific sh RNA caused decreases of α‐ SMA , MHC ‐ II , CD 40 and IL ‐4, and increases of E ‐cadherin and IFN ‐γ. These findings suggest that Notch1 is significantly associated with renal tubular and interstitial lesions. Notch1 can mediate HB x‐induced EMT of HK ‐2 cells, promote HB x‐induced increases in immune molecule expression and exacerbation of cytokine disorders, which may contribute to the progression of HBV ‐ GN . Inhibitors of Notch1 signalling may be useful as new therapeutics for the treatment of HBV ‐ GN .