Contraction of tubulointerstitial fibrosis tissue in diabetic nephropathy,as demonstrated in an in vitro fibrosis model |
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Authors: | Keisuke Ina Hirokazu Kitamura Shuji Tatsukawa Takashi Miyazaki Hirokazu Abe Yoshihisa Fujikura |
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Institution: | (1) Division of Morphological Analysis, Department of Anatomy, Biology and Medicine, Faculty of Medicine, Oita University, 1-1, Idaigaoka, Hasama-machi, Yufu, Oita, Japan |
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Abstract: | Tubulointerstitial fibrosis in diabetic nephropathy (DN) was investigated using an in vitro tissue model of remodeling, to
determine the pathogenic mechanism of fibrosis that leads to renal atrophy, i.e., renal failure. The remodeling model consisted
of a renal fibroblast-populated collagen lattice (FPCL). The overexpression of transforming growth factor (TGF)-β1 in the
diabetic kidney gave rise to FPCL contraction. FPCL relaxation was induced by the subsequent addition of cytochalasin D. The
FPCL failed to contract when exposed to TGF-β1 plus Y27632, a Rho kinase inhibitor. TGF-β1 induced the phosphorylation of
myosin light chains, and Y27632 blocked this activity. TGF-β1-induced FPCL contraction was suppressed by the addition of 2,3-butanedione
monoxime, a myosin ATPase inhibitor. As shown in the video, the contraction rate of the projections of the cells in the FPCL
was significantly greater in the TGF-β1 group than in the control group. Collectively, these results indicate that TGF-β1-induced
FPCL contraction is attributable to actin–myosin interactions in the fibroblasts through the activation of Rho kinase, the
phosphorylation of myosin light chains, and the subsequent activation of myosin ATPase. We propose that via these mechanisms,
tubulointerstitial fibrosis generates tissue contraction that leads to renal atrophy and renal failure in DN. |
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Keywords: | Diabetic nephropathy Tubulointerstitial fibrosis Fibroblast-populated collagen lattice Contraction Transforming growth factor β 1 |
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