Cytoresistance after acute kidney injury is limited to the recovery period of proximal tubule integrity and possibly involves Hippo‐YAP signaling. Issue 11 (14th June 2017)

• Record Type: Journal Article
• Authors: Iwakura, Takamasa; Fujigaki, Yoshihide; Fujikura, Tomoyuki; Tsuji, Takayuki; Ohashi, Naro; Kato, Akihiko; Yasuda, Hideo
• Is Part Of: Physiological reports. Volume 5:Issue 11(2017)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2017-06-14
• Subjects: Cytoresistance -- G1 arrest -- proximal tubule -- Survivin -- YAP; Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.13310
• Languages: English
• ISSNs: 2051-817X

Abstract

Abstract: 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. Abstract : Animals that had recovered from acute kidney injury (AKI) can obtain cytoresistance to subsequent insults with nephrotoxins and this phenomenon is termed acquired resistance to rechallenge injury. In this study, we examined the mechanisms of acquired cytoresistance from the aspect of Yes‐associated protein (YAP), a regulator of cell number and survivin, downstream mediator of YAP with antiapoptotic property in proximal tubule (PT). We clarified that upregulation of YAP in PT cells and its downstream mediator survivin were associated with cytoresistance of PT probably via antiapoptotic effect of survivin in the course of tubular recovery after AKI.