Dataset Information

RANTES mediates kidney ischemia reperfusion injury through a possible role of HIF-1? and LncRNA PRINS.

ABSTRACT: RANTES (Regulated on activation, normal T-cell expressed and secreted), recruits circulating leukocytes and augments inflammatory responses in many clinical conditions. Inflammatory responses in ischemia-reperfusion injury (IRI) significantly affect the unfavorable outcomes of acute kidney injury (AKI), and that infiltrating immune cells are important mediators of AKI. However, the significance of RANTES in AKI and whether hypoxia-induced LncRNAs are involved in the regulatory process of AKI are not known. Here we show that, in the kidney IRI mice model, significant RANTES expression was observed in renal tubular cells of wild type mice. RANTES deficient (RANTES(-/-)) mice showed better renal function by reducing the acute tubular necrosis, serum creatinine levels, infiltration of inflammatory cells and cytokine expressions compared to wild type. In vitro, we found that RANTES expression was regulated by NF-?B. Further, renal tubular cells showed deregulated LncRNA expression under hypoxia. Among HIF-1? dependent LncRNAs, PRINS (Psoriasis susceptibility-related RNA Gene Induced by Stress) was significantly up regulated in hypoxic conditions and had specific interaction with RANTES as confirmed through reporter assay. These observations show first evidence for RANTES produced by renal tubular cells act as a key chemokine in AKI and HIF-1? regulated LncRNA-PRINS might be involved in RANTES production.

SUBMITTER: Yu TM

PROVIDER: S-EPMC4698731 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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RANTES mediates kidney ischemia reperfusion injury through a possible role of HIF-1α and LncRNA PRINS.

Yu Tung-Min TM Palanisamy Kalaiselvi K Sun Kuo-Ting KT Day Yuan-Ji YJ Shu Kuo-Hsiung KH Wang I-Kuan IK Shyu Woei-Cherng WC Chen Ping P Chen Yuh-Lien YL Li Chi-Yuan CY

Scientific reports 20160104

RANTES (Regulated on activation, normal T-cell expressed and secreted), recruits circulating leukocytes and augments inflammatory responses in many clinical conditions. Inflammatory responses in ischemia-reperfusion injury (IRI) significantly affect the unfavorable outcomes of acute kidney injury (AKI), and that infiltrating immune cells are important mediators of AKI. However, the significance of RANTES in AKI and whether hypoxia-induced LncRNAs are involved in the regulatory process of AKI are ...[more]

PMID: 26725683

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Project description:Ischemic stroke is an acute and severe neurological disease with high mortality and disability rates worldwide. Polymerase I and transcript release factor (PTRF) plays a pivotal role in regulating cellular senescence, glucose intolerance, lipid metabolism, and mitochondrial bioenergetics, but its mechanism, characteristics, and functions in neuronal cells following the cerebral ischemia-reperfusion (I/R) injury remain to be determined. Methods: Transcription factor motif analysis, chromatin immunoprecipitation (ChIP), luciferase and co-Immunoprecipitation (co-IP) assays were performed to investigate the mechanisms of PTRF in neuronal cells after I/R injury. Lentiviral-sgRNA against PTRF gene was introduced to HT22 cells, and adeno-associated virus (AAV) encoding a human synapsin (hSyn) promoter-driven construct was transduced a short hairpin RNA (shRNA) against PTRF mRNA in primary neuronal cells and the cortex of the cerebral I/R mice for investigating the role of PTRF in neuronal damage and PLA2G4A change induced by the cerebral I/R injury. Results: Here, we reported that neuronal PTRF was remarkably increased in the cerebral penumbra after I/R injury, and HIF-1α and STAT3 regulated the I/R-dependent expression of PTRF via binding to its promoter in neuronal cells. Moreover, overexpression of neuronal PTRF enhanced the activity and stability of PLA2G4A by decreasing its proteasome-mediated degradation pathway. Subsequently, PTRF promoted reprogramming of lipid metabolism and altered mitochondrial bioenergetics, which could lead to oxidative damage, involving autophagy, lipid peroxidation, and ferroptosis via PLA2G4A in neuronal cells. Furthermore, inhibition of neuronal PTRF/PLA2G4A-axis markedly reduced the neurological deficits, cerebral infarct volumes, and mortality rates in the mice following cerebral I/R injury. Conclusion: Our results thus identify that the STAT3/HIF-1α/PTRF-axis in neurons, aggravating cerebral I/R injury by regulating the activity and stability of PLA2G4A, might be a novel therapeutic target for ischemic stroke.

Project description:AimReprogramming of glycometabolism plays a crucial role in the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). Sestrin2 (SESN2), a sensor upstream of the mTORC1, is closely related to glycometabolism. However, the effect and mechanism of SESN2 in CIRI are unclear. The goal of this research was to explore the effect of SESN2 on CIRI and its potential mechanisms related to glycometabolism.MethodsLentiviral vectors carrying SESN2 shRNA (Lenti-SESN2) or negative NC virus (Lenti-GFP) or rapamycin (mTOR inhibitor) were employed in the oxygen-glucose deprivation/reoxygenation (OGD/R) model and in the middle cerebral artery occlusion (MCAO) mice. In all, 3 days after I/R, neurological deficit scores and infarct size were assessed. The glycolysis and SESN2 levels were determined by RT-qPCR, Western blots, and immunofluorescence staining. Lactate levels were detected by a lactate assay kit, and the expression of the p-mTOR/HIF-1α signaling pathway was measured by immunofluorescence staining and protein blotting.ResultsLocal SESN2 deficiency in brain tissue increased the infarct size and reduced neurological scores 3 days after I/R. Moreover, the results showed that local SESN2 deficiency in brain tissue increased the expression of glycolysis-related proteins, including HK2, PFKM, PKM1, PKM2, and GLUT1. The lactate assay kit showed that local SESN2 deficiency in brain tissue increased lactate levels. In addition, local SESN2 deficiency in brain tissue improved the expression of the p-mTOR/HIF-1α pathway. However, rapamycin (RAP) treatment reversed these results, suggesting that SESN2 may influence IS injury by regulating glycometabolism via p-mTOR/HIF-1α pathway regulation. SESN2 knockdown in BV2 cells improved the glycolysis levels and the expression of the mTOR/HIF-1α pathway in the OGD/R model in vitro, but RAP treatment can also reverse these results.ConclusionsKnockdown of SESN2 in MCAO mice increased the expression of the p-mTOR/HIF-1α pathway, which increased glycolysis and lactate levels and, in turn, affected IS injury.

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RANTES mediates kidney ischemia reperfusion injury through a possible role of HIF-1? and LncRNA PRINS.

Publications

RANTES mediates kidney ischemia reperfusion injury through a possible role of HIF-1α and LncRNA PRINS.

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