Gene expression changes related to bone mineralization, blood pressure and lipid metabolism in mouse kidneys after space travel

Suzuki, Norio; Iwamura, Yuma; Nakai, Taku; Kato, Koichiro; Otsuki, Akihito; Uruno, Akira; Saigusa, Daisuke; Taguchi, Keiko; Suzuki, Mikiko; Shimizu, Ritsuko; Yumoto, Akane; Okada, Risa; Shimizu, Masaki; Shiba, Dai; Takahashi, Satoru; Suzuki, Takafumi; Yamamoto, Masayuki

doi:10.1016/j.kint.2021.09.031

Cited by 16 publications

(9 citation statements)

References 53 publications

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“…It has been shown that spaceflight activates the expression of Nrf2 target genes in various tissues and organs 18 , 20 . To address the question of whether this effect of spaceflight also occurs in the bone marrow and spleen, we compared the expression profiles of typical Nrf2 target genes in the four groups of mice, i.e ., GC-WT, FL-WT, GC-KO and FL-KO.…”

Section: Resultsmentioning

confidence: 99%

“…Through a series of the MHU-3 studies, we discovered that Nrf2 plays pivotal roles in maintaining lipid metabolism homoeostasis in response to spaceflight stress 8 , 20 , 21 . Considering that lipid serves as a fuel source for myelopoiesis in bone marrow 56 , it is plausible to hypothesise that the immunosuppression induced by spaceflight and Nrf2 deficiency may be mediated by disturbed lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

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Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy in mice

Shimizu,

Hirano,

Hasegawa

et al. 2023

Commun Biol

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Spaceflight-related stresses impact health via various body systems, including the haematopoietic and immune systems, with effects ranging from moderate alterations of homoeostasis to serious illness. Oxidative stress appears to be involved in these changes, and the transcription factor Nrf2, which regulates expression of a set of cytoprotective and antioxidative stress response genes, has been implicated in the response to spaceflight-induced stresses. Here, we show through analyses of mice from the MHU-3 project, in which Nrf2-knockout mice travelled in space for 31 days, that mice lacking Nrf2 suffer more seriously from spaceflight-induced immunosuppression than wild-type mice. We discovered that a one-month spaceflight-triggered the expression of tissue inflammatory marker genes in wild-type mice, an effect that was even more pronounced in the absence of Nrf2. Concomitant with induction of inflammatory conditions, the consumption of coagulation-fibrinolytic factors and platelets was elevated by spaceflight and further accelerated by Nrf2 deficiency. These results highlight that Nrf2 mitigates spaceflight-induced inflammation, subsequent immunosuppression, and thrombotic microangiopathy. These observations reveal a new strategy to relieve health problems encountered during spaceflight.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy in mice

Shimizu,

Hirano,

Hasegawa

et al. 2023

Commun Biol

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“…The Nrf2 knockout mice stayed there for 31 days and all the mice returned safely to the ground ( Suzuki et al, 2020b ). Analyses of the mice revealed that NRF2 acts to preserve homeostasis of the skeletal muscle, kidney, and epididymal white adipose tissue ( Hayashi et al, 2021 ; Suzuki et al, 2022 ; Uruno et al, 2021 ). Next challenge of the space mouse study is to verify that the NRF2 activation indeed acts to maintain homeostasis of whole body against the space stress and the study will continue.…”

Section: Future Perspectivesmentioning

confidence: 99%

Molecular Basis of the KEAP1-NRF2 Signaling Pathway

Suzuki

Takahashi

Yamamoto

2023

Molecules and Cells

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101

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Transcription factor NRF2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. NRF2 induces expression of detoxification and antioxidant enzymes and suppresses inductions of pro-inflammatory cytokine genes. KEAP1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of CULLIN 3 (CUL3)-based E3 ubiquitin ligase. KEAP1 regulates the activity of NRF2 and acts as a sensor for oxidative and electrophilic stresses. NRF2 has been found to be activated in many types of cancers with poor prognosis. Therapeutic strategies to control NRF2-overeactivated cancers have been considered not only by targeting cancer cells with NRF2 inhibitors or NRF2 synthetic lethal chemicals, but also by targeting host defense with NRF2 inducers. Understanding precise molecular mechanisms how the KEAP1-NRF2 system senses and regulates the cellular response is critical to overcome intractable NRF2-activated cancers.

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“…Recent animal studies in space have revealed how changes in renal function associated with blood pressure control and bone mineralization play an important role in adaptation to gravity changes. 40 Kidneys may also be central to achieving a healthy life in space.…”

Section: Peripheral Vascular Resistancementioning

confidence: 99%