Research Paper Volume 12, Issue 18 pp 18052—18072

Caloric restriction alleviates aging-related fibrosis of kidney through downregulation of miR-21 in extracellular vesicles

Jin-rui Liu1,2, , Guang-yan Cai1, , Yi-chun Ning1, , Jing-chao Wang1, , Yang Lv1, , Ya-nan Guo1, , Bo Fu1, , Quan Hong1, , Xue-feng Sun1, , Xiang-mei Chen1, ,

  • 1 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, Chinese PLA General Hospital, Beijing 100853, China
  • 2 Renal Transplant Division, Department of Nephrology, Zhengzhou No. 7 People's Hospital, Zhengzhou 450017, Henan, China

Received: October 29, 2019       Accepted: April 27, 2020       Published: August 27, 2020
How to Cite

Copyright: © 2020 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Glomerulosclerosis and renal interstitial fibrosis occur with the aging kidney. In this study, we examined the expression of miR-21, peroxisome proliferator-activated receptor(PPARα), hypoxia-inducible factor(HIF-1α) in the kidney of 3-month-old rats fed ad libitum (YAL), 24-month-old rats fed ad libitum (OAL) and 24-month-old rats subjected to a 70% calorie-restricted diet for 8 months (OCR). We found long-term caloric restriction (CR) ameliorated aging and aging-related fibrosis. CR ameliorated the increment of miR-21 and HIF-1α, as well as the decrement of PPARα in old ad libitum group. Human proximal tubular cells (HPTCs) presented phenotypes of senescence and epithelial to mesenchymal transition (EMT) under high-glucose conditions, in which senescence occurred earlier than EMT. Senescent cells secreted extracellular vesicles (EVs) which contained miR-21 into the recipient cells. Inhibiting miR-21 of donor cells prevented the occurrence of EMT in recipient cells. In addition, miR-21 induced EMT through targeting PPARα protein and consequently enhancing HIF-1α expression, although other pathways cannot be ruled out. These findings demonstrated that miR-21-containing EVs derived from the senescent cells could facilitate EMT of HPTCs via PPARα-HIF-1α signaling pathway. Long-term caloric restriction and caloric restriction mimetics alleviated aging-related-fibrosis of kidney through downregulation of miR-21.


PPARα: peroxisome proliferator-activated receptor; HIF-1α: hypoxia-inducible factor; EMT: epithelial to mesenchymal transition; EVs: extracellular microvesicles; SASP: senescence-associated secretory phenotype; HG: high glucose.