Alleviation of senescence and epithelial-mesenchymal transition in aging kidney by short-term caloric restriction and caloric restriction mimetics via modulation of AMPK/mTOR signaling.
Renal fibrosis contributes to declining renal function in the elderly. What is unclear however, is whether epithelial-mesenchymal transition (EMT) contributes to this age-related renal fibrosis. Here, we analyzed indicators of EMT during kidney aging and investigated the protective effects and mechanisms of short-term regimens of caloric restriction (CR) or caloric restriction mimetics (CRMs), including resveratrol and metformin. High glucose was used to induce premature senescence and EMT in human primary proximal tubular cells (PTCs) in vitro. To test the role of AMPK-mTOR signaling, siRNA was used to deplete AMPK. Cellular senescence and AMPK-mTOR signaling markers associated with EMT were detected. CR or CRMs treatment alleviated age-related EMT in aging kidneys, which was accompanied by activation of AMPK-mTOR signaling. High glucose induced premature senescence and EMT in PTCs in vitro, which was accompanied by down-regulation of AMPK/mTOR signaling. CRMs alleviated high glucose-induced senescence and EMT via stimulation of AMPK/mTOR signaling. Activation of AMPK/mTOR signaling protected PTCs from high glucose-induced EMT and cellular senescence. Short-term regimens of CR and CRMs alleviated age-related EMT via AMPK-mTOR signaling, suggesting a potential approach to reducing renal fibrosis during aging.
Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing, P. R. China.|Department of Nephrology, First Hospital of Jilin University, Changchun, Jilin, P. R. China.
Dan
D
Dong
Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing, P. R. China.
Guang-Yan
GY
Cai
Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing, P. R. China.
Yi-Chun
YC
Ning
Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing, P. R. China.
Jing-Chao
JC
Wang
Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing, P. R. China.
Yang
Y
Lv
Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing, P. R. China.
Quan
Q
Hong
Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing, P. R. China.
Shao-Yuan
SY
Cui
Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing, P. R. China.
Bo
B
Fu
Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing, P. R. China.
Ya-Nan
YN
Guo
Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing, P. R. China.
Xiang-Mei
XM
Chen
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000375:Aging / Q000187:drug effects*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015153:Blotting, Western; D031204:Caloric Restriction; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007004:Hypoglycemic Agents; D013267:Stilbenes; D008687:Metformin; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D000077185:Resveratrol
AMPK/mTOR signaling; Gerotarget; caloric restriction mimetics; epithelial-mesenchymal transition; senescence; short-term caloric restriction