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Notch signaling in the collecting duct regulates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction in mice

  • Choi, Arum (Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea) ;
  • Nam, Sun Ah (Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea) ;
  • Kim, Wan-Young (Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea) ;
  • Park, Sang Hee (Institute of Clinical Medicine Research of Bucheon St. Mary's Hospital) ;
  • Kim, Hyang (Division of Nephrology, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Yang, Chul Woo (Department of Internal Medicine, College of Medicine, The Catholic University of Korea) ;
  • Kim, Jin (Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea) ;
  • Kim, Yong Kyun (Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea)
  • Received : 2016.07.15
  • Accepted : 2016.09.24
  • Published : 2018.07.01

Abstract

Background/Aims: Mind bomb-1 (Mib1) encodes an E3 ubiquitin ligase, which is required for the initiation of Notch signaling. Recently, it was demonstrated that the renal collecting duct plays an important role in renal fibrosis. Here, we investigated the role of Notch signaling in renal fibrosis using conditional knockout mice with the specific ablation of Mib1 in renal collecting duct principal cells. Methods: Mib1-floxed mice ($Mib1^{f/f}$) were crossed with aquaporin 2 (AQP2)-Cre mice in order to generate principal cell-specific Mib1 knockout mice ($Mib1^{f/f}$:AQP2-$Cre^+$). Unilateral ureteral obstruction (UUO) was performed, and mice were sacrificed 7 days after UUO. Results: After performing the UUO, renal tubulointerstitial fibrosis and the expression of transforming growth factor ${\beta}$ were markedly enhanced in the obstructed kidneys of $Mib1^{f/f}$ mice compared with the sham-operated kidney of $Mib1^{f/f}$ mice. These changes were shown to be even more pronounced in the obstructed kidneys of $Mib1^{f/f}$ :AQP2-$Cre^+$ mice than in those of the $Mib1^{f/f}$ mice. Furthermore, the number of TUNNEL-positive cells in renal collecting duct was higher in the obstructed kidneys of $Mib1^{f/f}$ :AQP2-$Cre^+$ mice than in the kidneys of $Mib1^{f/f}$ mice. Conclusions: Notch signaling in the renal collecting duct plays an important role in the regulation of renal tubulointerstitial fibrosis and apoptosis after UUO.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea (NRF), MRC, institute of Clinical Medicine Research of Bucheon St. Mary's Hospital

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