Abstract
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.
Highlights
According to the data from the United States Renal Data System, the number of patients on maintenance dialysis will double over the few years, and a relatively large number of the patients newly diagnosed with chronic kidney disease (CKD) each year are elderly [1]
Decades of research have associated age-related loss of kidney function with increased renal vascular resistance, reduced renal plasma flow, increased filtration fraction, lower GFR, and progressive structural and functional deterioration of the kidney. Both primary proximal tubular cells (PTC) senescence and tubulointerstitial fibrosis are known to contribute to age-associated loss of kidney function
Aging kidneys are characterized by common hallmarks of cellular senescence, including increased expression of P16
Summary
According to the data from the United States Renal Data System, the number of patients on maintenance dialysis will double over the few years, and a relatively large number of the patients newly diagnosed with chronic kidney disease (CKD) each year are elderly [1]. Similar results have been reported for another CRM, the stilbene derivative resveratrol, which has been shown to inhibit senescence in endothelial progenitor cells [13] and WI-38 fibroblasts [14], and to reduce epidermal growth factor-induced EMT in MCF-7 cells [15] These observations notwithstanding, the effects of short-term regimens of CR and CRM on cellular senescence and EMT in the aging kidney remain unknown. After short-term CR or metformin treatment, renal expression of both Zeb and α-SMA was lower in the OCR and OMET groups than in the OAL group, whereas renal expression of E-cadherin showed the opposite trend (Figure 1) These results indicate that EMT was more www.impactjournals.com/oncotarget. Induction of E-cadherin expression and AMPK/ mTOR signaling, and repression of P16, P21, Zeb and α-SMA expression, were observed in the high glucose plus CRM (metformin or resveratrol) co-stimulated cells compared to cells stimulated with HG alone (Figure 5). These results indicate that metformin and resveratrol alleviate EMT and senescence via AMPK/mTOR signaling, and that activation of AMPK/mTOR protected PTCs from high glucose-induced EMT and cellular senescence
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