HGF alleviates high glucose-induced injury in podocytes by GSK3β inhibition and autophagy restoration

Zhang, Congying; Hao, Bo; Yu, Siying; Chen, Qi; Zhang, Nong; Li, Hui

doi:10.1016/j.bbamcr.2016.08.004

Cited by 24 publications

(19 citation statements)

References 25 publications

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“…The present study also showed that downregulation of the expression of E2F1 significantly suppressed the expression of AMPKα2 and mTORc1, suggesting that the downregulation of E2F1 inhibited HG-induced apoptosis, and reversed the inhibition of mTORc1-mediated autophagy. Taken together, these results confirmed that increased autophagy within certain limits suppressed HG-induced cellular damage (34,35).…”

Section: Discussionsupporting

confidence: 74%

Overexpression of miR‑17‑5p protects against high glucose‑induced endothelial cell injury by targeting E2F1‑mediated suppression of autophagy and promotion of apoptosis

Yao

Xue

2018

Int J Mol Med

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E2 promoter binding factor 1 (E2F1) has been reported to have an important regulatory role in cell survival during hyperglycemic conditions; however, the mechanisms remain to be fully elucidated. Bioinformatics analyses have suggested that microRNA (miR)‑17‑5p targets the 3'untranslated region (3'UTR) of E2F1. The aim of the present study was to characterize the protective effect of miR‑17‑5p/E2F1 on human umbilical vein endothelial cells (HUVECs) under high glucose (HG) conditions, to confirm the regulatory effect of miR‑17‑5p on E2F1/AMP‑activated protein kinase α2 (AMPKα2)‑mediated apoptosis and E2F1/mammalian target of rapamycin complex 1 (mTORC1)‑mediated autophagy. Bifluorescein experiments were performed to characterize the interaction between miR‑17‑5p and E2F1. The Cell Counting Kit‑8 assay, flow cytometry, immunofluorescence, and reverse transcription‑quantitative polymerase chain reaction and western blot analyses were used to detect cell viability, apoptosis, autophagy, and relative mRNA and protein expression, respectively. The results showed that HG induced the downregulation of miR‑17‑5p and upregulation of E2F1 during HUVEC injury. The downregulation of E2F1 inhibited HG‑induced HUVEC dysfunction by suppressing mTORC1‑mediated inhibition of autophagy and AMPKα2‑mediated promotion of apoptosis. The results suggested that inhibiting the expression of E2F1 protected against HG‑induced HUVEC injury via the activation of autophagy. The overexpression of miR‑17‑5p inhibited E2F1‑mediated HUVEC injury under HG conditions, which was reversed following transfection with an E2F1‑overexpression vector. The bifluorescein experiments showed that miR‑17‑5p targeted the 3'UTR of E2F1. Taken together, the results suggested that the expression of miR‑17‑5p inhibited HG‑induced endothelial cell injury by targeting E2F1.

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Section: Discussionsupporting

confidence: 74%

Overexpression of miR‑17‑5p protects against high glucose‑induced endothelial cell injury by targeting E2F1‑mediated suppression of autophagy and promotion of apoptosis

Yao

Xue

2018

Int J Mol Med

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“…It is intuitive to use a high glucose-induced model to mimic the DM condition to study autophagy because high glucose levels are key characteristics of DM. However, negative [24], suppressive [27][28][29], and stimulatory [30][31][32] effects of high glucose on podocyte autophagy have been reported. These contrasting results indicate that other interfering factors may be involved in regulating autophagy.…”

Section: Discussionmentioning

confidence: 99%

Advanced glycation end‐products suppress autophagic flux in podocytes by activating mammalian target of rapamycin and inhibiting nuclear translocation of transcription factor EB

Zhao

Chen

Tan

et al. 2018

The Journal of Pathology

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Insufficient autophagy in podocytes is related to podocyte injury in diabetic nephropathy (DN). Advanced glycation end‐products (AGEs) are major factors of podocyte injury in DN. However, the role and mechanism of AGEs in autophagic dysfunction remain unknown. We investigated autophagic flux in AGE‐stimulated cultured podocytes using multiple assays: western blotting, reverse transcription–quantitative PCR, immunofluorescence staining, and electron microscopy. We also utilized chloroquine and a fluorescent probe to monitor the formation and turnover of autophagosomes. Mice of the db/db strain were used to model diabetes mellitus (DM) with high levels of AGEs. To mimic DM with normal levels of AGEs as a control, we treated db/db mice with pyridoxamine to block AGE formation. AGEs impaired autophagic flux in the cultured podocytes. Compared with db/db mice with normal AGEs but high glucose levels, db/db mice with high AGEs and high glucose levels exhibited lower autophagic activity. Aberrant autophagic flux was related to hyperactive mammalian target of rapamycin (mTOR), a major suppressor of autophagy. Pharmacologic inhibition of mTOR activity restored impaired autophagy. AGEs inhibited the nuclear translocation and activity of the pro‐autophagic transcription factor EB (TFEB) and thus suppressed transcription of its several autophagic target genes. Conversely, TFEB overexpression prevented AGE‐induced autophagy insufficiency. Attenuating mTOR activity recovered TFEB nuclear translocation under AGE stimulation. Co‐immunoprecipitation assays further demonstrated the interaction between mTOR and TFEB in AGE‐stimulated podocytes and in glomeruli from db/db mice. In conclusion, AGEs play a crucial part in suppressing podocyte autophagy under DM conditions. AGEs inhibited the formation and turnover of autophagosomes in podocytes by activating mTOR and inhibiting the nuclear translocation of TFEB. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…Glycogen synthase kinase 3 beta (GSK-3β) is a constitutively activated Ser/Thr protein kinase that regulates glycogen metabolism, gene expression, and apoptosis [16]. It plays a pivotal role in mitochondria-mediated cell death.…”

Section: Introductionmentioning

confidence: 99%

Ischemic Postconditioning Alleviates Intestinal Ischemia-Reperfusion Injury by Enhancing Autophagy and Suppressing Oxidative Stress through the Akt/GSK-3β/Nrf2 Pathway in Mice

Chen

Zhang

Lan

et al. 2020

Oxidative Medicine and Cellular Longevity

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Aims. Ischemic postconditioning (IPO) has a strong protective effect against intestinal ischemia-reperfusion (IIR) injury that is partly related to autophagy. However, the precise mechanisms involved are unknown. Methods. C57BL/6J mice were subjected to unilateral IIR with or without IPO. After 45 min ischemia and 120 min reperfusion, intestinal tissues and blood were collected for examination. HE staining and Chiu's score were used to evaluate pathologic injury. We test markers of intestinal barrier function and oxidative stress. Finally, we used WB to detect the expression of key proteins of autophagy and the Akt/GSK-3β/Nrf2 pathway. Results. IPO significantly attenuated IIR injury. Expression levels of LC3 II/I, Beclin-1, and p62 were altered during IIR, indicating that IPO enhanced autophagy. IPO also activated Akt, inhibited GSK-3β, induced Nrf2 nuclear translocation, and upregulated HO-1 and NQO1 expression, thus providing protective effects against IIR injury by suppressing oxidative stress. Consistently, the beneficial effects of IPO were abolished by pretreatment with 3-methyladenine, SC66, and brusatol, potent inhibitors of autophagy, Akt, and Nrf2, respectively. Conclusion. Our study indicates that IPO can ameliorate IIR injury by evoking autophagy, activating Akt, inactivating GSK-3β, and activating Nrf2. These findings may provide novel insights for the alleviation of IIR injury.

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HGF alleviates high glucose-induced injury in podocytes by GSK3β inhibition and autophagy restoration

Cited by 24 publications

References 25 publications

Overexpression of miR‑17‑5p protects against high glucose‑induced endothelial cell injury by targeting E2F1‑mediated suppression of autophagy and promotion of apoptosis

Overexpression of miR‑17‑5p protects against high glucose‑induced endothelial cell injury by targeting E2F1‑mediated suppression of autophagy and promotion of apoptosis

Advanced glycation end‐products suppress autophagic flux in podocytes by activating mammalian target of rapamycin and inhibiting nuclear translocation of transcription factor EB

Ischemic Postconditioning Alleviates Intestinal Ischemia-Reperfusion Injury by Enhancing Autophagy and Suppressing Oxidative Stress through the Akt/GSK-3β/Nrf2 Pathway in Mice

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