Augmenter of liver regeneration regulates autophagy in renal ischemia–reperfusion injury via the AMPK/mTOR pathway

Pu, Tao; Liao, Xiaohui; Sun, Hang; Guo, Hui; Jiang, Xiao; Peng, Junbo; Zhang, Ling; Liu, Qi

doi:10.1007/s10495-017-1370-6

Cited by 23 publications

(17 citation statements)

References 48 publications

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“…Phosphorylation of AMPKα on threonine 172 (pT172) is required for full activation. Recent studies have reported that AMPK is the main initiator of stress‐triggered autophagy, which works through suppressing mTOR by activation of tuberous sclerosis complex 2 and direct phosphorylation of mTORC1 or unc‐51 like autophagy activating kinase 1 . In our study, we showed that GSK3β inhibition induces the phosphorylation of AMPK both in liver I/R and in primary hepatocyte H/R, as well as suppression of mTOR activity.…”

Section: Discussionsupporting

confidence: 63%

Inhibition of glycogen synthase kinase 3β protects liver against ischemia/reperfusion injury by activating 5′ adenosine monophosphate‐activated protein kinase‐mediated autophagy

Kong

Hua

Qin

et al. 2018

Hepatology Research

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Aim: Autophagy has been found to play an important role in hepatic ischemia/reperfusion (I/R) injury. Our previous study has also clarified that rictor deficiency aggravated hepatic I/R injury by suppressing autophagy. Here, we explore whether autophagy participates in glycogen synthase kinase 3β (GSK3β)mediated cytoprotection in liver I/R. Methods:Mice were treated with SB216763 to inhibit GSK3β before being subjected to hepatic I/R. Liver injury was evaluated by liver and blood samples. Autophagy was measured by detecting expression of microtubule-associated protein 1 light chain-3B (LC3B) II and autophagy protein 5 (ATG-5), as well as the number of autophagosomes by transmission electron microscope. Primary hepatocytes pretreated with SB216763 for 2 h were subjected to hypoxia/reoxygenation to induce autophagy. The lactate dehydrogenase level was used to evaluate cell death and survival. Autophagy inhibitors and 5 0 adenosine monophosphate-activated protein kinase (AMPK) inhibitor were given in vivo or in vitro. Results: SB216763 significantly increased the number of autophagosomes and the protein levels of LC3B II and ATG-5 in liver I/R models, which was accompanied by a decline of hepatic necrosis and apoptosis. Consistent with the in vivo study, autophagy and cytoprotection were induced by the inhibition of GSK3β in the in vitro study. Moreover, pretreatment with autophagy inhibitors attenuated the cytoprotective role of autophagy in the GSK3β-treated liver I/R models. Further analysis showed that pretreatment with an AMPK inhibitor increased mammalian target of rapamycin (mTOR) activity, decreased autophagy, and abrogated GSK3β-mediated liver protection.Conclusion: Autophagy was induced by GSK3β inhibition through the AMPK/mTOR pathway and could substantially ameliorate liver I/R injury. Therefore, our findings strongly renew the therapeutic value of the GSK3β/autophagy axis in hepatic I/R injury.

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Section: Discussionsupporting

confidence: 63%

Inhibition of glycogen synthase kinase 3β protects liver against ischemia/reperfusion injury by activating 5′ adenosine monophosphate‐activated protein kinase‐mediated autophagy

Kong

Hua

Qin

et al. 2018

Hepatology Research

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“…When activated by certain stress, AMPK regulates sugars and fatty acids that are good or detrimental to the heart. For example, targeting AMPK phosphorylation is known to protect against ischemia reperfusion-induced injury [1,2]. The mammalian target of rapamycin complex 1 (mTORC1) has a central role among the intracellular signal transduction pathways adapting growth, metabolism and aging [3].…”

Section: Introductionmentioning

confidence: 99%

The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy

Zhang

Zhao

Quan

et al. 2017

Biochemical and Biophysical Research Communications

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AMP-activated protein kinase (AMPK), an enzyme that plays a role in cellular energy homeostasis, modulates myocardial signaling in the heart. Myocardial dysfunction is a common complication of sepsis. Autophagy is involved in the aging related cardiac dysfunction. However, the role of AMPK in sepsis-induced cardiotoxicity has yet to be clarified, especially in aging. In this study, we explored the role of AMPK in lipopolysaccharide (LPS)-induced myocardial dysfunction and elucidated the potential mechanisms of AMPK/mTOR pathway regulating autophagy in young and aged mice. We harvested cardiac tissues by intraperitoneal injection of LPS treatment. The results by echocardiography, pathology, contractile and intracellular Ca2+ property as well as western blot analysis revealed that LPS induced remarkable cardiac dysfunction and cardiotoxicity in mice hearts and cardiomyocytes, which were more seriously in the aged mice. Western blot analysis indicated that the underlying mechanisms included inhibition autophagy mediated by AMPK/mTOR activation. LPS overtly promoted the expression of AMPK upstream regulator PP2A and PP2Cα. Pharmacological activation of AMPK improved cardiac function and upregulated cardiac autophagy induced by LPS in the aged mice. Collectively, our findings suggest that upregulation of autophagy by administration of AMPK could attenuate LPS-induced cardiotoxicity, which enhances our knowledge to explore new drugs and strategies for combating cardiac dysfunction induced by sepsis.

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“…This indicates that tubule-specific c-met signaling plays an essential role in renal protection due to its proliferative, antiapoptotic, and anti-inflammatory properties. [71][72][73] Consistently, HGF/c-met attenuates renal injury and inflammation while accelerating repair after glycerol-induced AKI. 74 IGF and IGFBPs in AKI IGF, a peptide growth factor that is secreted by the collecting duct of the adult kidney, binds with IGF1R and phosphorylates insulin receptor substrate proteins, thereby initiating downstream pathways, including PI3K-Akt-mTOR, to participate in the regulation of cell proliferation and apoptosis 75,76 (Fig.…”

Section: Egf and The Egf Receptor In Akimentioning

confidence: 84%

Potential targeted therapy and diagnosis based on novel insight into growth factors, receptors, and downstream effectors in acute kidney injury and acute kidney injury-chronic kidney disease progression

Gao

Zhong

Jin

et al. 2020

Sig Transduct Target Ther

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Acute kidney injury (AKI) is defined as a rapid decline in renal function and is characterized by excessive renal inflammation and programmed death of resident cells. AKI shows high morbidity and mortality, and severe or repeated AKI can transition to chronic kidney disease (CKD) or even end-stage renal disease (ESRD); however, very few effective and specific therapies are available, except for supportive treatment. Growth factors, such as epidermal growth factor (EGF), insulin-like growth factor (IGF), and transforming growth factor-β (TGF-β), are significantly altered in AKI models and have been suggested to play critical roles in the repair process of AKI because of their roles in cell regeneration and renal repair. In recent years, a series of studies have shown evidence that growth factors, receptors, and downstream effectors may be highly involved in the mechanism of AKI and may function in the early stage of AKI in response to stimuli by regulating inflammation and programmed cell death. Moreover, certain growth factors or correlated proteins act as biomarkers for AKI due to their sensitivity and specificity. Furthermore, growth factors originating from mesenchymal stem cells (MSCs) via paracrine signaling or extracellular vesicles recruit leukocytes or repair intrinsic cells and may participate in AKI repair or the AKI-CKD transition. In addition, growth factor-modified MSCs show superior therapeutic potential compared to that of unmodified controls. In this review, we summarized the current therapeutic and diagnostic strategies targeting growth factors to treat AKI in clinical trials. We also evaluated the possibilities of other growth factorcorrelated molecules as therapeutic targets in the treatment of AKI and the AKI-CKD transition.

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Augmenter of liver regeneration regulates autophagy in renal ischemia–reperfusion injury via the AMPK/mTOR pathway

Cited by 23 publications

References 48 publications

Inhibition of glycogen synthase kinase 3β protects liver against ischemia/reperfusion injury by activating 5′ adenosine monophosphate‐activated protein kinase‐mediated autophagy

Inhibition of glycogen synthase kinase 3β protects liver against ischemia/reperfusion injury by activating 5′ adenosine monophosphate‐activated protein kinase‐mediated autophagy

The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy

Potential targeted therapy and diagnosis based on novel insight into growth factors, receptors, and downstream effectors in acute kidney injury and acute kidney injury-chronic kidney disease progression

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