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HIF-1? Mediates TRAIL-Induced Neuronal Apoptosis via Regulating DcR1 Expression Following Traumatic Brain Injury.

ABSTRACT: Background: Neuronal apoptosis involved in secondary injury following traumatic brain injury (TBI) significantly contributes to the poor outcomes of patients with TBI. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis of tumor cells. Hypoxia factor (HIF) 1? is a controversial factor that mediates the neuronal apoptotic pathway. Herein, we hypothesize that HIF-1? may mediate the TRAIL-induced neuronal apoptosis after TBI. Methods: We used Western blots and immunofluorescence to study the expression and cell localization of TRAIL and death receptor 5 (DR5) after TBI in rats. Soluble DR5 (sDR5) administration was used to block the TRAIL-induced neuronal death and neural deficits. HIF-1? inhibitor 2ME and agonist DMOG were used to study the role of HIF-1? in TRAIL-induced neuronal death. Meanwhile, HIF-1? siRNA was used to investigate the role of HIF-1? in TRAIL-induced neuronal death in vitro. Results: The expressions of microglia-located TRAIL and neuron-located DR5 were significantly upregulated after TBI. sDR5 significantly attenuated TRAIL-induced neuronal apoptosis and neurological deficits. 2ME decreased neuronal apoptosis, lesion area, and brain edema and improved neurological function via increased expression of TRAIL decoy receptor 1 (DcR1), which inhibited TRAIL-induced apoptosis after TBI. The administration of DMOG produced the opposite effect than did 2ME. Similarly, HIF-1? siRNA attenuated TRAIL-induced neuronal death via increased DcR1 expression in vitro. Conclusion: Our findings suggested that the TRAIL/DR5 signaling pathway plays an important role after neuronal apoptosis after TBI. HIF-1? mediates TRAIL-induced neuronal apoptosis by regulating DcR1 expression following TBI.

SUBMITTER: Fang Y

PROVIDER: S-EPMC7416670 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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HIF-1α Mediates TRAIL-Induced Neuronal Apoptosis via Regulating DcR1 Expression Following Traumatic Brain Injury.

Fang Yuanjian Y Lu Jianan J Wang Xiaoyu X Wu Haijian H Mei Shuhao S Zheng Jingwei J Xu Shenbin S Lenahan Cameron C Chen Sheng S Zhang Jianmin J Hong Yuan Y

Frontiers in cellular neuroscience 20200803

Background: Neuronal apoptosis involved in secondary injury following traumatic brain injury (TBI) significantly contributes to the poor outcomes of patients with TBI. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis of tumor cells. Hypoxia factor (HIF) 1α is a controversial factor that mediates the neuronal apoptotic pathway. Herein, we hypothesize that HIF-1α may mediate the TRAIL-induced neuronal apoptosis after TBI. Methods: W ...[more]

PMID: 32848609

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Project description:AbstractContrast-induced acute kidney injury (CI-AKI) causes clinically acquired nephropathy in patients who undergo coronary interventions. Hypoxic injury to proximal tubular epithelial cells is a pathological mechanism of CI-AKI. Previous studies have shown that hypoxia activates HIF-1α/HE4/NF-κB to enhance renal fibrosis, and the SGLT-2 inhibitor luseogliflozin inhibits hypoxia-inducible factor (HIF)-1α expression to reduce the progression of diabetic nephropathy. However, the therapeutic effects and mechanisms of SGLT-2 inhibitors on CI-AKI are unclear. We explored the role of the HIF-1α/HE4/NF-κB pathway in CI-AKI and how dapagliflozin effectively treats CI-AKI by inhibiting this pathway. In vitro, cells were divided into the control, hypoxia, hypoxia + dapagliflozin, and hypoxia + pSilencer-HIF-1α groups. Cellular hypoxia, apoptosis, and related protein expression were evaluated by immunofluorescence, western blotting, and flow cytometry, respectively. Dapagliflozin significantly decreased oxygen consumption, HIF-1α, human epididymis protein 4 (HE4), NF-κB expression, and apoptotic cells compared with the control (P < 0.01). In vivo, rats were divided into the control (C), diabetes (D), diabetes + contrast media, and diabetes + contrast media + dapagliflozin groups. Rats in the latter 2 groups were treated with dapagliflozin for 2 days. CI-AKI was induced by intravenously injecting indomethacin, N-nitro-l-arginine methyl ester, and iohexol. The effects of dapagliflozin on CI-AKI rats were elucidated by assessing renal function, H&E staining, and immunohistochemistry. Serum creatinine, urea nitrogen, TUNEL-positive tubular cells, HIF-1α, HE4, NF-κB expression, and histopathological scores were increased in diabetes + contrast media rats compared with C, D, and diabetes + dapagliflozin + contrast media rats (P < 0.01). Thus, dapagliflozin may ameliorate CI-AKI through suppression of HIF-1α/HE4/NF-κB signaling in vitro and in vivo.

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HIF-1? Mediates TRAIL-Induced Neuronal Apoptosis via Regulating DcR1 Expression Following Traumatic Brain Injury.

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HIF-1α Mediates TRAIL-Induced Neuronal Apoptosis <i>via</i> Regulating DcR1 Expression Following Traumatic Brain Injury.

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