The AKT/mTOR pathway mediates neuronal protective effects of erythropoietin in sepsis

Abstract

Sepsis is one of the most common causes of mortality in intensive care units. Although sepsis-associated encephalopathy (SAE) is reported to be a leading manifestation of sepsis, its pathogenesis remains to be elucidated. In this study, we investigated whether exogenous recombinant human erythropoietin (rhEPO) could protect brain from neuronal apoptosis in the model of SAE. We showed that application of rhEPO enhanced Bcl-2, decreased Bad in lipopolysaccharide treated neuronal cultures, and improved neuronal apoptosis in hippocampus of cecal ligation and peroration rats. We also found that rhEPO increased the expression of phosphorylated AKT, and the antiapoptotic role of rhEPO could be abolished by phosphoinositide 3-kinase (PI3K)/AKT inhibitor LY294002 or SH-5. In addition, systemic sepsis inhibited the hippocampal-phosphorylated mammalian target of rapamycin (mTOR) and p70S6K (downstream substrates of PKB/AKT signaling), which were restored by administration of exogenous rhEPO. Moreover, treatment with mTOR-signaling inhibitor rapamycin or transfection of mTOR siRNA reversed the neuronal protective effects of rhEPO. Finally, exogenous rhEPO rescued the emotional and spatial cognitive defects without any influence on locomotive activity. These results illustrated that exogenous rhEPO improves brain dysfunction by reducing neuronal apoptosis, and AKT/mTOR signaling is likely to be involved in this process. Application of rhEPO may serve as a potential therapy for the treatment of SAE.

MicroRNA-138 Aggravates Inflammatory Responses of Macrophages by Targeting SIRT1 and Regulating the NF-κB and AKT Pathways

“…In the present study, the increased activation of the AKT pathway was accompanied by decreased inflammatory cytokines, further supporting the idea that AKT participates in the activation of M2 macrophages 34. Additionally, the present study is consistent with recent studies showing that AKT plays a protective role in sepsis [35][36][37]. SIRT1 shows strong anti-inflammation activity [38].…”

Systemic Lipopolysaccharide Administration-Induced Cognitive Impairments are Reversed by Erythropoietin Treatment in Mice

“…In addition to its known function in erythropoiesis, EPO has been reported to exert antiapoptotic, antiinflammatory, antioxidative, and neurotrophic properties [6]. EPO is an important mediator of the adaptive response to metabolic stress, which is an endogenous mediator of neuroprotection in various central nervous system disorders [7][8][9]. Accumulating evidence has demonstrated that exogenous EPO is beneficial during systemic sepsis.…”

WISP1: Clinical Insights for a Proliferative and Restorative Member of the CCN Family

“…The growth factor and cytokine erythropoietin (EPO) activates Akt through its phosphorylation of serine 473 [70, 71] and prevents vascular cell demise through silent mating type information regulator 2 homolog 1 (SIRT1) cell longevity pathways [72]. EPO utilizes Akt to block cell injury during Aβ exposure [26], promote the survival of retinal ganglion cells during N-methyl-d-aspartate (NMDA) toxicity [73], enhance the myocardial protective function of mobilized peripheral blood mononuclear cells [74], foster anti-inflammatory effects [75], protect against sepsis [76], limit renal cell injury [77], and limit cellular injury during models of oxidative stress [78–81]. Similar to EPO, other trophic factors also rely upon the PI 3-K and Akt pathways to foster cellular survival during toxic environments such as insulin-like growth factor-1 (IGF-1) [56], insulin [82], and brain derived neurotrophic factor [83].…”

“…mTORC2 also includes mLST8 and Deptor, but has additional components that are Rictor (Rapamycin-Insensitive Companion of mTOR), the mammalian stress-activated protein kinase interacting protein (mSIN1), and the protein observed with Rictor-1 (Protor-1) [136, 137]. Similar to WISP1, mTOR signaling is associated with PI 3-K, Akt, forkhead transcription factors, PRAS40, AMP activated protein kinase (AMPK), and p70 ribosomal S6 kinase (p70S6K) to affect cellular survival through programmed cell death pathways that involve apoptosis, autophagy, and necroptosis [60, 62, 63, 76, 79, 139–149]. For example, Akt can control mTORC1 activity through the modulation of hamartin (tuberous sclerosis 1)/tuberin (tuberous sclerosis 2) (TSC1/TSC2) complex, an inhibitor of mTORC1 [150–152].…”