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Transient myofibroblast differentiation of interstitial fibroblastic cells relevant to tubular dilatation in uranyl acetate-induced acute renal failure in rats

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Abstract

To investigate the mechanisms of myofibroblast differentiation of interstitial fibroblastic cells (FCs) in rats with uranyl acetate-induced acute renal failure (ARF), we examined the relationship between the expression of α-smooth muscle actin (α-SMA), myofibroblast phenotype and tubular dilatation as well as cell shape and adhesion of FCs. Peritubular α-SMA-positive myofibroblasts appeared after induction of ARF and extended along the damaged, dilated proximal tubules and then almost disappeared after proximal tubular recovery. The perimeter of proximal tubules correlated with fractional areas stained for α-SMA (P<0.001). Most α-SMA-positive cells did not incorporate [3H]-thymidine, indicating a low proliferative activity. Transmission electron microscopy showed that FCs increasingly attached to the tubular basement membrane by elongated cytoplasm-containing microfilament bundles, which formed abundant adherens and gap junctions from day 4 to day 7. Scanning electron microscopy showed hypertrophic FCs covering large areas of tubules after induction of ARF. Administration of chlorpromazine, which can inhibit cytoskeletal movement, after induction of ARF partially inhibited myofibroblast differentiation of FCs immunohistochemically and morphologically and resulted in more dilated proximal tubules in concert with aggravation of renal dysfunction and inhibition of regenerative repair at day 4 than vehicle-administered rats. Our results indicate that mechanical tension, judged by tubular dilatation, may contribute to the induction of α-SMA phenotype with increased stress fiber formation and intercellular junctions in FCs to support damaged nephron structures by adjusting tensional homeostasis in rats with uranyl acetate-induced ARF.

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Acknowledgements

This work was partially supported by a Grant-In-Aid for scientific research (C; No.13671107) from the Ministry of Education, Science, Sports and Culture, Japan.

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Authors and Affiliations

  1. First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, 431-3192, Hamamatsu , Japan

    Yoshihide Fujigaki, Difei Sun, Tetsuo Goto, Hua Zhou, Masanori Sakakima, Hirotaka Fukasawa, Tatsuo Yamamoto & Akira Hishida

  2. Research Equipment Center, Hamamatsu University School of Medicine, 431-3192, Hamamatsu , Japan

    Yoshinori Muranaka

  3. Hemodialysis Unit, Hamamatsu University School of Medicine, 431-3192, Hamamatsu , Japan

    Katsuhiko Yonemura

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  1. Yoshihide Fujigaki
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  2. Yoshinori Muranaka
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  10. Akira Hishida
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Correspondence to Yoshihide Fujigaki.

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Fujigaki, Y., Muranaka, Y., Sun, D. et al. Transient myofibroblast differentiation of interstitial fibroblastic cells relevant to tubular dilatation in uranyl acetate-induced acute renal failure in rats. Virchows Arch 446, 164–176 (2005). https://doi.org/10.1007/s00428-004-1155-5

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  • DOI: https://doi.org/10.1007/s00428-004-1155-5

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