Rapamycin does not act as a dietary restriction mimetic in the protection against ischemia reperfusion injury

IntroductionShort-term fasting protects against renal ischemia reperfusion injury (IRI). mTOR signaling is downregulated and may be involved in its protective effect. Rapamycin is considered a possible mimetic as it inhibits the mTOR-pathway. This study examines the effect of rapamycin on renal IRI. MethodsMice were divided in four groups : Ad libitum(AL), Fasted (F), AL treated with rapamycin (AL+R) and F treated with rapamycin (F+R). Rapamycin was administered intraperitoneally 24h before bilateral renal IRI was induced. Survival was monitored for 7 days. Renal cell death, regeneration, and mTOR activity were determined 48h after reperfusion. Oxidative stress resistance of HK-2 and PTEC cells after rapamycin treatment was determined. ResultsAll F and F+R mice survived the experiment. Although rapamycin substantially downregulated mTOR-activity, survival in the AL+R group was similar to AL (10%). Renal regeneration was significantly reduced in AL+R but not in F+R. After IRI (48h), pS6K/S6K ratio was lower in F, F+R and AL+R groups compared to AL fed animals (p=0.02). In vitro, rapamycin also significantly downregulated mTOR-activity (p<0.001), but did not protect against oxidative stress. ConclusionRapamycin pretreatment does not protect against renal IRI. Thus, protection against renal IRI by fasting is not exclusively mediated through inhibition of mTOR activity, but may involve preservation of regenerative mechanisms despite mTOR downregulation. Therefore, rapamycin cannot be used as a dietary mimetic to protect against renal IRI.