Rapamycin Does Not Act as a Dietary Restriction Mimetic in the Protection against Ischemia Reperfusion Injury
Eline van den Akker1, Frank J M F Dor2, Jan N M IJzermans2
1Division of Hepatobiliary and Transplant Surgery, Department of Surgery, Rotterdam Transplant Institute, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, ekvandenakker@gmail.com.
Introduction:
Short-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.
Material And Methods:
Mice were divided into four groups: ad libitum (AL), fasted (F), AL treated with rapamycin (AL+R), and F treated with rapamycin (F+R). Rapamycin was administered intraperitoneally 24 h before bilateral renal IRI was induced. Survival was monitored for 7 days. Renal cell death, regeneration, and mTOR activity were determined 48 h after reperfusion. Oxidative stress resistance of human renal proximal tubular and human primary tubular epithelial cells after rapamycin treatment was determined.
Results:
All 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 (48 h), 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.
Conclusion:
Rapamycin 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.
Insights
Short-term fasting protects against kidney injury, but rapamycin, a drug that mimics fasting by inhibiting mTOR, does not offer protection. Fasting
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Short-term fasting confers protection against renal ischemia reperfusion injury (IRI).
- Mammalian target of rapamycin (mTOR) signaling is downregulated during fasting and may mediate its protective effects.
- Rapamycin, an mTOR inhibitor, is investigated as a potential mimetic for fasting's protective effects on renal IRI.
Purpose of the Study:
- To investigate the effect of rapamycin on renal ischemia reperfusion injury (IRI) in mice.
- To determine if rapamycin can mimic the protective effects of fasting against renal IRI.
- To elucidate the role of mTOR signaling in the protective mechanisms of fasting against renal IRI.
Main Methods:
- Mice were assigned to ad libitum (AL), fasted (F), AL with rapamycin (AL+R), or F with rapamycin (F+R) groups.
- Rapamycin was administered 24 hours before inducing bilateral renal IRI.
- Survival, renal cell death, regeneration, mTOR activity, and oxidative stress resistance were assessed.
Main Results:
- All fasted mice (F and F+R) survived, while survival in the AL+R group was similar to AL (10%).
- Rapamycin significantly downregulated mTOR activity in all groups but did not protect against renal IRI in ad libitum-fed mice.
- Renal regeneration was impaired in AL+R mice but preserved in F+R mice, suggesting fasting's protection involves mechanisms beyond mTOR inhibition.
Conclusions:
- Rapamycin pretreatment does not protect against renal IRI.
- Fasting's protection against renal IRI is not solely mediated by mTOR inhibition.
- Fasting may preserve regenerative mechanisms, independent of mTOR downregulation, highlighting its unique protective role against renal IRI.
