P0100CALORIC RESTRICTION ALLEVIATES AGING-RELATED FIBROSIS OF KIDNEY THROUGH MIR-21 DOWNREGULATION IN EXTRACELLULAR VESICLES

Abstract

Abstract Background and Aims The mechanism of renal interstitial fibrosis occurs with kidney aging is unknown. Caloric restriction and caloric restriction mimetics (CRM) alleviate aging-related-fibrosis. The aim of this study is to investigate whether extracellular microvesicles (EVs) derived from senescent cells facilitate fibrosis development in aging kidney and the potential signalling pathway involved in the process. Method In this study, animal experiments included 3-mon-old ad libitum(YAL) rats, 24-mon-old ad libitum(OAL) rats and 24-mon-old caloric restriction(OCR) rats, which was given 70% of OAL’s for 8 months. Senescent cells were induced in proximal tubular epithelial cells(PTCs) by high glucose and further treated with resveratrol as CRM. The expression of miR-21, peroxisome proliferator-activated receptor(PPARα), hypoxia-inducible factor(HIF1α) in the kidney of rats and PTCs were examined. Epithelial to mesenchymal transition (EMT) and the related signalling pathway were detected by up- or down-regulation of miR-21, respectively. Results Long-term caloric restriction ameliorated senescent changes and aging-related fibrosis in aged ad libitum rat kidney. Caloric restriction blunted the increased expressions of miR-21 and HIF1α, the decreased expression of PPARα in renal tissue of old rats. High glucose induced PTCs senesence phenotype and EMT. miR-21 was detected in extracellular vesicles secreted by senescent PTC cells. CRMs resveratrol prevented EMT through downregulation of miR-21 in extracellular vesicles from the senescent PTC cells. Further, inhibiting miR-21 of donor senescent cells prevented the occurrence of EMT in recipient PTC cells. Finally, miR-21 induced EMT mainly through targeting PPARα protein and enhancing HIF1α expression. Conclusion This study demonstrated that miR-21-containing extracellular microvesicles derived from the senescent cells could facilitate tubular phenotype transition of neighbouring PTC cells via PPARα-HIF1α signalling pathway. Long-term caloric restriction and caloric restriction mimetics alleviate aging-related renal fibrosis through downregulation of miR-21 excretion.