The Effect of mTOR-Inhibition on NF-κB Activity in Kidney Ischemia-Reperfusion Injury in Mice

Kezic, Aleksandra; Becker, Jan U.; Thaiss, Friedrich

doi:10.1016/j.transproceed.2013.02.110

Cited by 27 publications

(22 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inhibition of mTORC1 by aPC is congruent with AMPK activation (an inhibitor of mTORC1 signaling) by aPC after myocardial infarction. 21 mTORC1 activation in IRI has frequently been observed, 58,59 corroborating a mechanistic relevance of mTORC1 inhibition by aPC. We acknowledge that the role of mTOR signaling in myocardial IRI is complex and depends on its temporal activation pattern, the cell type, the extent of mTOR activity, and the involvement of mTORC1 vs mTORC2.…”

Section: 5152mentioning

confidence: 66%

Cytoprotective activated protein C averts Nlrp3 inflammasome–induced ischemia-reperfusion injury via mTORC1 inhibition

Nazir

Gadi

Al‐Dabet

et al. 2017

Blood

143

129

View full text Add to dashboard Cite

show abstract

Section: 5152mentioning

confidence: 66%

Cytoprotective activated protein C averts Nlrp3 inflammasome–induced ischemia-reperfusion injury via mTORC1 inhibition

Nazir

Gadi

Al‐Dabet

et al. 2017

Blood

143

129

View full text Add to dashboard Cite

show abstract

“…An in vitro study confirms that mTORi lead to activation of NF‐κB, and subsequently to increased expression of the adhesion molecule ICAM‐1 by the endothelium, resulting in increased tissue infiltration by leukocytes . A study in mice confirmed that sirolimus stimulates the production of NF‐κB‐driven proinflammatory cytokines such as TNF‐α and IL‐1β …”

Section: Mtor Inhibitor‐induced Interstitial Lung Disease: Current Stmentioning

confidence: 74%

mTOR inhibitor‐induced interstitial lung disease in cancer patients: Comprehensive review and a practical management algorithm

Willemsen¹,

Grutters

Gerritsen³

et al. 2015

Intl Journal of Cancer

View full text Add to dashboard Cite

Mammalian target of rapamycin inhibitors (mTORi) have clinically significant activity against various malignancies, such as renal cell carcinoma and breast cancer, but their use can be complicated by several toxicities. Interstitial lung disease (ILD) is an adverse event of particular importance. Mostly, mTORi-induced ILD remains asymptomatic or mildly symptomatic, but it can also lead to severe morbidity and even mortality. Therefore, careful diagnosis and management of ILD is warranted. The reported incidence of mTORi-induced ILD varies widely because of a lack of uniform diagnostic criteria and active surveillance. Because of the nonspecific clinical features, a broad differential diagnosis that includes (opportunistic) infections should be considered in case of suspicion of mTORi-induced ILD. The exact mechanism or interplay of mechanisms leading to the development of ILD remains to be defined. Suggested mechanisms are either a direct toxic effect or immune-mediated mechanisms, considering mTOR inhibitors have several effects on the immune system. The clinical course of ILD varies widely and is difficult to predict. Consequently, the discrimination between when mTOR inhibitors can be continued safely and when discontinuation is indicated is challenging. In this review, we give a comprehensive review of the incidence, clinical presentation and pathophysiology of mTORi-induced ILD in cancer patients. We present newly developed diagnostic criteria for ILD, which include clinical symptoms as well as basic pulmonary function tests and radiological abnormalities. In conjunction with these diagnostic criteria, we provide a detailed and easily applicable clinical management algorithm. Mechanism of action of mTOR inhibitorsThe phosphatidylinositol 3-kinase (PI3K), Akt, mammalian target of rapamycin (mTOR) pathway plays a central role in the control of the growth of cells, tissues and organisms. This pathway physiologically is activated by a variety of upstream signals, such as nutrients, hypoxia, stress and growth factors. Pathologically, several genetic events can lead to constitutional activation of this pathway and in many malignancies it is overactive. mTOR is a key kinase in this pathway, which forms two distinct protein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). When activated, mTORC1 induces mRNA transcription and the translation of numerous proteins stimulating cell cycle progression and subsequently driving cell growth, division and metabolism and inhibiting apoptosis. In addition, angiogenesis is stimulated by production of hypoxia-inducible factor 1 (HIF-1) and HIF-2 alpha and subsequently vascular endothelial growth factor (VEGF). As a result, the activation of mTORC1 leads to cell division, angiogenesis, cell survival and as such promotes cancer development. 1-3 mTORC2 not only controls the actin cytoskeleton but also phosphorylates and activates Akt, an important regulator of cell survival.Rapamycin (also known as sirolimus) and its analogs (temsirolimus and everolimus) specifically...

show abstract

“…However, MAP kinases and PI3K/Akt/mTOR sig naling are thought to be implicated in the initiation and progression of IRinduced inflammatory responses (51)(52)(53)(54). We first examined the impact of aloperine on MAP kinase activities.…”

Section: Discussionmentioning

confidence: 99%

Aloperine Protects Mice against Ischemia-Reperfusion (IR)-Induced Renal Injury by Regulating PI3K/AKT/mTOR Signaling and AP-1 Activity

Zhang

et al. 2015

Mol Med

View full text Add to dashboard Cite

Aloperine is a quinolizidine alkaloid extracted from the leaves of Sophora plants. It has been recognized with the potential to treat inflammatory and allergic diseases as well as tumors. In this report, we demonstrate that pretreatment with aloperine provided protection for mice against ischemia-reperfusion (IR)-induced acute renal injury as manifested by the attenuated inflammatory infiltration, reduced tubular apoptosis, and well-preserved renal function. Mechanistic studies revealed that aloperine selectively repressed IL-1β and IFN-γ expression by regulating PI3K/Akt/mTOR signaling and NF-κB transcriptional activity. However, aloperine did not show a perceptible impact on IL-6 and TGF-β expression and the related Jak2/Stat3 signaling. It was also noted that aloperine regulates AP-1 activity, through which it not only enhances SOD expression to increase reactive oxygen species (ROS) detoxification but also promotes the expression of antiapoptotic Bcl-2, thereby preventing tubular cells from IR-induced apoptosis. Collectively, our data suggest that administration of aloperine prior to IR insults, such as renal transplantation, could be a viable approach to prevent IR-induced injuries.

show abstract

The Effect of mTOR-Inhibition on NF-κB Activity in Kidney Ischemia-Reperfusion Injury in Mice

Cited by 27 publications

References 29 publications

Cytoprotective activated protein C averts Nlrp3 inflammasome–induced ischemia-reperfusion injury via mTORC1 inhibition

Cytoprotective activated protein C averts Nlrp3 inflammasome–induced ischemia-reperfusion injury via mTORC1 inhibition

mTOR inhibitor‐induced interstitial lung disease in cancer patients: Comprehensive review and a practical management algorithm

Aloperine Protects Mice against Ischemia-Reperfusion (IR)-Induced Renal Injury by Regulating PI3K/AKT/mTOR Signaling and AP-1 Activity

Contact Info

Product

Resources

About