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.
Highlights
Animals that have recovered from acute kidney injury (AKI) can develop cytoresistance to subsequent nephrotoxin insults, and this phenomenon is termed acquired resistance to rechallenge injury (Honda et al 1987)
We found that acquired cytoresistance in proximal tubule (PT) cells is limited to the period before normalization of cell number and subcellular molecular integrity, from a hyperplastic state to baseline levels after uranyl acetate (UA)-induced AKI
It has been reported that Yesassociated protein (YAP) is activated during tissue regeneration after hepatectomy, and that nuclear YAP was transiently activated even after the liver reached prehepatectomy size (Grijalva et al 2014); this was shown to result in liver hyperplasia following hepatectomy (Islami et al 1959)
Summary
Animals that have recovered from acute kidney injury (AKI) can develop cytoresistance to subsequent nephrotoxin insults, and this phenomenon is termed acquired resistance to rechallenge injury (Honda et al 1987). This phenomenon of resistance to injury after prior exposure and subsequent recovery has been shown by many investigators in diverse forms of injury, including ischemia/ reperfusion (Nowak et al 2004; Kapitsinou and Haase 2015), oxidants (Nowak et al 2012), and alkylating agents (Vaidya et al 2003; Korrapati et al 2005, 2006).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
