N‐myc downstream‐regulated gene 2 protects blood–brain barrier integrity following cerebral ischemia

Takarada-Iemata, Mika; Yoshikawa, Akifumi; Ta, Hieu Minh; Okitani, Nahoko; Nishiuchi, Takumi; Aida, Yasuhiro; Kamide, Tomoya; Hattori, Tsuyoshi; Ishii, Hiroshi; Tamatani, Takashi; Le, Thuong Manh; Roboon, Jureepon; Kitao, Yasuko; Matsuyama, Tomohiro; Nakada, Mitsutoshi; Hori, Osamu

doi:10.1002/glia.23315

Cited by 39 publications

(29 citation statements)

References 49 publications

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“…Increasing or rescuing the expression of NDRG2 in WT and Ndrg2 −/− mice significantly reduces the infarct volume, neurological outcome, and interstitial glutamate levels, suggesting a potentially therapeutic target for brain ischemia. A recent study reported that the loss of NDRG2 increases astrocytic MMP activity and BBB permeability, which exacerbate subsequent brain damage after permanent focal cerebral ischemia [45]. This is consistent with the function of NDRG2 as a neuroprotective protein observed in the present study, although we focused on astrocyte-mediated glutamate uptake but not astrocyteassociated blood cell infiltration and BBB permeability.…”

Section: Discussionsupporting

confidence: 92%

NDRG2 Protects the Brain from Excitotoxicity by Facilitating Interstitial Glutamate Uptake

Yin

Guo

Tao

et al. 2019

Transl. Stroke Res.

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Glutamate is a prominent neurotransmitter responsible for excitatory synaptic transmission and is taken up by sodium-dependent excitatory amino acid transporters (EAATs) on astrocytes to maintain synaptic homeostasis. Here, we report that N-myc downstream regulated gene 2 (NDRG2), a known tumor suppressor, is required to facilitate astroglial glutamate uptake and protect the brain from glutamate excitotoxicity after ischemia. NDRG2 knockout (Ndrg2 −/−) mice exhibited an increase in cerebral interstitial glutamate and a reduction in glutamate uptake into astrocytes. The ability of NDRG2 to control EAAT-mediated glutamate uptake into astrocytes required NDRG2 to interact with and promote the function of Na + /K +-ATPase β1, which could be disrupted by a Na + /K +-ATPase β1 peptide. The deletion of NDRG2 or treatment with the Na + /K +-ATPase β1 peptide significantly increased neuronal death upon a glutamate challenge and aggravated brain damage after ischemia. Our findings demonstrate that NDRG2 plays a pivotal role in promoting astroglial glutamate uptake from the interstitial space and protecting the brain from glutamate excitotoxicity.

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Section: Discussionsupporting

confidence: 92%

NDRG2 Protects the Brain from Excitotoxicity by Facilitating Interstitial Glutamate Uptake

Yin

Guo

Tao

et al. 2019

Transl. Stroke Res.

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“…Previous studies have demonstrated that the tumor suppressor NDRG2 has a neuroprotective function in various diseases ( 29 , 30 ). Therefore, the present study investigated whether NDRG2 was involved in the regulation of cerebral ischemic injury and necroptosis.…”

Section: Resultsmentioning

confidence: 99%

NDRG2 attenuates ischemia-induced astrocyte necroptosis via the repression of RIPK1

et al. 2020

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Cerebral ischemia results in severe brain damage, and is a leading cause of death and long-term disability. Previous studies have investigated methods to activate astrocytes in order to promote repair in injured brain tissue and inhibit cell death. It has previously been shown that N-myc downstream-regulated gene 2 (NDRG2) was highly expressed in astrocytes and associated with cell activity, but the underlying mechanism is largely unknown. The present study generated NDRG2 conditional knockout ( Ndrg2 -/-) mice to investigate whether NDRG2 can block ischemia-induced astrocyte necroptosis by suppressing receptor interacting protein kinase 1 (RIPK1) expression. This study investigated astrocyte activity in cerebral ischemia, and identified that ischemic brain injuries could trigger RIP-dependent astrocyte necroptosis. The depletion of NDRG2 was found to accelerate permanent middle cerebral artery occlusion-induced necroptosis in the brain tissue of Ndrg2 -/- mice, indicating that NDRG2 may act as a neuroprotector during cerebral ischemic injury. The present study suggested that NDRG2 attenuated astrocytic cell death via the suppression of RIPK1. The pharmacological inhibition of astrocyte necroptosis by necrostatin-1 provided neuroprotection against ischemic brain injuries after NDRG2 knockdown. Therefore, NDRG2 could be considered as a potential target for the treatment of cerebral ischemia.

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“…In addition, NDRG2 was implicated in the ischemic stress response in several in vivo and in vitro studies [72][73][74][75][76][77][78]. Temporal and spatial patterns of NDRG2 expression in the rat brain were investigated after transient middle cerebral artery occlusion and reperfusion.…”

Section: Ndrg2 In Brain Tumors and Other Nervous System Diseasesmentioning

confidence: 99%

N-Myc Downstream-Regulated Gene 2 (NDRG2) as a Novel Tumor Suppressor in Multiple Human Cancers

Zhang¹,

Li²,

Shen³

et al. 2019

Genes and Cancer

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N-myc downstream-regulated gene 2 (NDRG2) was identified as a novel tumor suppressor gene in regulating the proliferation, differentiation, apoptosis and metastasis of multiple cancer types. Consistent with this finding, we and other groups observed the decreased NDRG2 expression in multiple human cancer cell lines and tumors, including breast cancer, colorectal cancer, and cervical cancer. We identified NDRG2 as a stress sensor for hypoxia, DNA damage stimuli and endoplasmic reticulum stress (ERS). Our recent data showed that NDRG2 could promote the differentiation of colorectal cancer cells. Interestingly, we found that reduced NDRG2 expression was a powerful and independent predictor of poor prognosis of colorectal cancer patients. Furthermore, NDRG2 can inhibit epithelial-mesenchymal transition (EMT) by positively regulating E-cadherin expression. Moreover, NDRG2-deficient mice show spontaneous development of various tumor types, including T-cell lymphomas, providing in vivo evidence that NDRG2 functions as a tumor suppressor gene. We believe that NDRG2 is a novel tumor suppressor and might be a therapeutic target for cancer treatment.Genes and Cancer 2 carcinoma cells [8]. Moreover, NDRG2-deficient mice show spontaneous development of various tumor types, providing in vivo evidence that NDRG2 functions as a tumor suppressor gene. In this chapter, we will introduce the recent findings of NDRG2 as tumor suppressor in vitro and in vivo, and also the detailed mechanism. NDRG2 as a hypoxia and DNA damage responderOur group firstly identified NDRG2 as a protein containing an acyl-carrier protein (ACP)-like domain. The gene was cloned from differentially expressed genes between glioblastoma and normal brain tissues using PCR-based subtractive hybridization in 2003. NDRG2, NDRG1, NDRG3, and NDRG4 comprise the NDRG gene family [1] and share approximately 59-68% homology. Additionally, NDRG family members display over 92% homology between humans and mice.The expression and cellular localization of NDRG2 were altered following exposure to different stresses, supporting the role of NDRG2 as a cellular stress sensor. Wang et al. found that NDRG2 expression was markedly upregulated in several cancer cell lines exposed to hypoxic conditions or similar stresses at both the mRNA and protein levels [9]. Hypoxia-inducible factor-1α (HIF-1α) can directly bind to hypoxia response elements (HREs) in the NDRG2 promoter, thus upregulating NDRG2 expression under hypoxia. Importantly, enforcing the expression of NDRG2 can strongly increase the apoptosis of cancer cells. Alternatively, NDRG2 can translocate from the cytoplasm to the nucleus under DNA damage stress. However, no explicit nuclear localization signal (NLS) sequence has been identified in the NDRG2 protein. Although NLSs are the most common type of nuclear import elements, other mechanisms may also be involved in NDRG2 translocation. For example, Liu et al. and Cao et al. confirmed that NDRG2 was upregulated by p53 or adriamycin (ADR) treatment [10,11]. Thus, NDRG2 can tra...

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N‐myc downstream‐regulated gene 2 protects blood–brain barrier integrity following cerebral ischemia

Cited by 39 publications

References 49 publications

NDRG2 Protects the Brain from Excitotoxicity by Facilitating Interstitial Glutamate Uptake

NDRG2 Protects the Brain from Excitotoxicity by Facilitating Interstitial Glutamate Uptake

NDRG2 attenuates ischemia-induced astrocyte necroptosis via the repression of RIPK1

N-Myc Downstream-Regulated Gene 2 (NDRG2) as a Novel Tumor Suppressor in Multiple Human Cancers

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