Open AccessCytoresistance after acute kidney injury is limited to the recovery period of proximal tubule integrity and possibly involves Hippo‐YAP signaling
Author(s) -
Iwakura Takamasa,
Fujigaki Yoshihide,
Fujikura Tomoyuki,
Tsuji Takayuki,
Ohashi Naro,
Kato Akihiko,
Yasuda Hideo
Publication year - 2017
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.13310
Subject(s) - survivin , acute kidney injury , apoptosis , medicine , creatinine , flow cytometry , cell cycle , kidney , proximal tubule , andrology , urology , endocrinology , chemistry , immunology , cancer , biochemistry
Rat proximal tubule ( PT ) cells that have recovered from severe acute kidney injury induced by uranyl acetate ( UA ) develop cytoresistance to subsequent UA treatments. We reported that enhanced G1 arrest might contribute to cytoresistance. Herein, we examined these mechanisms by investigating Yes‐associated protein ( YAP ), a regulator of cell number, and survivin, a downstream mediator of YAP that inhibits apoptosis. Rats pretreated with saline (vehicle group) or UA ( AKI group) were injected with UA 2 weeks, 2 months, or 6 months after treatment. Cytoresistance, evaluated by serum creatinine, was observed at 2 weeks, was attenuated at 2 months, and was lost at 6 months in the AKI group. Based on immunohistochemistry, overexpressed YAP /survivin in PT cells and an increased number of PT cells was found before the second insult at 2 weeks, regressed gradually, and returned to a normal value by 6 months in the AKI group. Cell cycle status, assessed by flow cytometry, was equivalent in all groups before the second insult. However, early G1 phase (cyclin D1−) and p27+ PT cells increased in the AKI group compared to those in the vehicle group until 2 months, but were comparable to those in the vehicle group at 6 months. p21+ PT cells increased at 2 weeks, but normalized by 2 months. Thus, PT cells that have recovered from AKI transiently overexpress YAP /survivin, probably inhibiting apoptosis and resulting in acquired cytoresistance. This effect occurs until PT remodeling is complete, subceullular PT integrity is restored, and cell numbers are normalized.