Halofuginone prevents extracellular matrix deposition in diabetic nephropathy |
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Authors: | Seiya Sato Minoru Takemoto Masaki Fujimoto Masaya Koshizaka Aki Watanabe Karin Halevi Koutaro Yokote |
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Institution: | a Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan b Department of Drug Information and Communication, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan c Collgard Biopharmaceuticals, Herzliya, Israel |
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Abstract: | Transforming growth factor-β (TGF-β) is known to promote the accumulation of extracellular matrix (ECM) and the development of diabetic nephropathy. Halofuginone, an analog of febrifugine, has been shown to block TGF-β1 signaling and subsequent type I collagen production. Here, the inhibitory effect of halofuginone on diabetic nephropathy was examined. Halofuginone suppressed Smad2 phosphorylation induced by TGF-β1 in cultured mesangial cells. In addition, the expression of TGF-β type 2 receptor decreased by halofuginone. Halofuginone showed an inhibitory effect on type I collagen and fibronectin expression promoted by TGF-β1. An in vivo experiment using db/db mice confirmed the ability of halofuginone to suppress mesangial expansion and fibronectin overexpression in the kidneys. Moreover, an analysis of urinary 8-OHdG level and dihydroethidium fluorescence revealed that halofuginone reduced oxidative stress in the glomerulus of db/db mice. These data indicate that halofuginone prevents ECM deposition and decreases oxidative stress, thereby suppressing the progression of diabetic nephropathy. |
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Keywords: | Halofuginone Diabetic nephropathy TGF-β Type I collagen Fibronectin TGF-β type 2 receptor Mesangial cell Oxidative stress |
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