title: The deposition of Notch1 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.
abstract: 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 Notch1 may be involved in the progression of HBV-GN. In this study, we evaluated the distribution of Notch1 in patients with HBV-GN. Our results showed that Notch1 was mainly distributed in renal tubules and the interstitial area, and the expression levels of Notch1 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 (HBx) gene using a eukaryotic vector. HBx expression resulted in significantly increased detection of Notch1, alpha-smooth muscle actin (α-SMA), major histocompatibility complex-II (MHC-II), CD40 and interleukin-4 (IL-4). At the same time, E-cadherin and interferon-γ (IFN-γ) expression levels were significantly inhibited. These HBx-induced phenotypes were exacerbated by upregulation of Notch1. Knock-down of Notch1 by specific shRNA caused decreases of α-SMA, MHC-II, CD40 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 HBx-induced EMT of HK-2 cells, promote HBx-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.
authors.affiliation: Department of Nephrology, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.forename: N
authors.initials: N
authors.lastname: Zhu
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: L-J
authors.initials: LJ
authors.lastname: Gu
authors.forename: W-J
authors.initials: WJ
authors.lastname: Yuan
mesh_terms: D002460:Cell Line; D054338:Cell Transdifferentiation; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000502:physiology*; D005921:Glomerulonephritis / Q000473:pathology*; D019694:Hepatitis B, Chronic / Q000150:complications*; D054884:Host-Pathogen Interactions; D006801:Humans; D007668:Kidney / Q000473:pathology; D051881:Receptor, Notch1 / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D016207:Cytokines; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein
keywords: Notch1; epithelial-mesenchymal transdifferentiation; hepatitis B virus X; immune molecules; renal tubular epithelial cells