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  • Title: Transdifferentiation of cultured tubular cells induced by hypoxia.
    Author: Manotham K, Tanaka T, Matsumoto M, Ohse T, Inagi R, Miyata T, Kurokawa K, Fujita T, Ingelfinger JR, Nangaku M.
    Journal: Kidney Int; 2004 Mar; 65(3):871-80. PubMed ID: 14871406.
    Abstract:
    BACKGROUND: Tubulointerstitial fibrosis leads to progressive kidney disease and, ultimately, may result in end-stage renal disease (ESRD). Myofibroblasts, which express alpha-smooth muscle actin (alpha-SMA) in their cytoplasm, regulate renal fibrogenesis. Recent studies suggest that certain interstitial myofibroblasts derive from renal tubular cells that have undergone epithelial-mesenchymal transformation (EMT) (transdifferentiation). However, the role(s) of hypoxia, which is involved in progressive kidney disease, on tubular EMT remains unclear. METHODS: Immortalized rat proximal tubular cells (IRPTC) were cultured in normobaric hypoxia (1% O2) for 3, 6, or 15 days, with match control in normoxic conditions. alpha-SMA, vimentin, and desmin chosen as markers of EMT were measured by immunocytochemistry and immunoblots collagen I production and cell motility were chosen as functional assays. Various concentrations of cobaltous chloride (CoCl2) were used as hypoxic mimickers. In vivo studies were carried out in a chronic ischemic kidney model. RESULTS: Immunohistochemical studies revealed increased expression of alpha-SMA. Striking morphologic changes were detected after 6 days of hypoxia for alpha-SMA-positive fibroblast-like cells (SMA + fib) and after 15 days for alpha-SMA-positive myofibroblast-like cells (SMA + myo). Immunoblots confirmed these findings. Collagen I production increased in a time-dependent manner parallel to alpha-SMA expression. Cell motility assays demonstrated that transformed cells had higher migratory capacity than normal tubular cells. Cobaltous salt also induced alpha-SMA and collagen I synthesis. Chronic ischemic kidney revealed in vivo tubular EMT at day 7. CONCLUSION: Hypoxia can induce tubular EMT. This process may play an important role in progression of kidney disease.
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