Cellular and molecular mechanisms associated with ischemic stroke severity in female mice with chronic kidney disease

Hénaut, Lucie; Grissi, Maria; Brazier, François; Assem, Maryam; Poirot-Leclercq, Sabrina; Lenglet, Gaëlle; Boudot, Cédric; Avondo, Carine; Boullier, Agnès; Choukroun, Gabriel; Massy, Ziad A.; Kamel, Saı̈d; Chillon, Jean‐Marc

doi:10.1038/s41598-019-42933-0

Cited by 24 publications

(35 citation statements)

References 41 publications

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“…Uremic toxins are waste products of microbiota that can cross the intestinal blood–barrier because of increased gut permeability after AIS, and thus reach the systemic circulation ( 98 ). In support of a purported gut–brain–kidney axis, an experimental study demonstrated that rats affected by both acute kidney injury and AIS displayed neuronal loss; glial, macrophage, and microglial upsurge; and increased circulating IL-6 and IL-1β levels ( 99 ). Following a systemic inflammatory process, high level of microbiota waste products such as TMAO are found in patients with chronic kidney disease, suggesting that TMAO is inversely associated with glomerular filtration rate and should be considered as a new clinical marker of renal medullary damage, hypertension, and heart disease ( 100 ).…”

Section: Discussionmentioning

confidence: 99%

Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications

et al. 2020

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The microbiota-gut-brain axis is considered a central regulator of the immune system after acute ischemic stroke (AIS), with a potential role in determining outcome. Several pathways are involved in the evolution of gut microbiota dysbiosis after AIS. Brain-gut and gut-brain signaling pathways involve bidirectional communication between the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, the enteric nervous system, and the immune cells of the gut. Alterations in gut microbiome can be a risk factor and may also lead to AIS. Both risk factors for AIS and gut-microbiome composition are influenced by similar factors, including diabetes, hypertension, hyperlipidemia, obesity, and vascular dysfunction. Furthermore, the systemic inflammatory response after AIS may yield liver, renal, respiratory, gastrointestinal, and cardiovascular impairment, including the multiple organ dysfunction syndrome. This review focus on biochemical, immunological, and neuroanatomical modulation of gut microbiota and its possible systemic harmful effects after AIS, as well as the role of ischemic stroke on microbiota composition. Finally, we highlight the role of gut microbiota as a potential novel therapeutic target in acute ischemic stroke.

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Section: Discussionmentioning

confidence: 99%

Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications

et al. 2020

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“…International Publisher kappa-light-chain-enhancer of activated B cells) signaling, are activated in the pathogenesis of CRF [8][9][10][11][12]. Of these pathways, TGF-β-mediated signaling plays a central role [8][9][10][11][12]. Elevated levels of TGF-β have been found in CRF patients and in animal models in many laboratories [13][14][15].…”

Section: Ivyspringmentioning

confidence: 99%

Transforming growth factor beta (TGF-β) is activated by the CtBP2-p300-AP1 transcriptional complex in chronic renal failure

Zhou¹,

Wan²,

Zou³

et al. 2020

Int. J. Biol. Sci.

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Chronic renal failure (CRF), also known as chronic kidney disease (CKD), is a common renal disorder characterized by gradual kidney dysfunction. Molecular dissection reveals that transforming growth factor beta (TGF-β) plays a central role in the pathogenesis of CRF. However, the mechanism underlying TGF-β upregulation has not been demonstrated. Here, we verified that the elevated level of TGF-β was associated with the severity of CRF stages and the activation of TGF-β-mediated signaling in 120 renal biopsies from CRF patients. By analyzing the promoter region of the TGFB1 gene, we identified one AP-1 (activator protein 1) and four NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) binding sites. Knockdown of two AP-1 subunits (c-Jun and c-FOS) or blockage of AP-1 signaling with two inhibitors T-5224 and SR11302 could cause the downregulation of TGFB1, whereas knockdown of two NF-κB subunits (p65 and p50) or blockage of NF-κB signaling with two inhibitors TPCA1 and BOT-64 could not change the expression of TGFB1. Using mass spectrometry and coimmunoprecipitation analyses, we found that both c-Jun and c-FOS formed a complex with CtBP2 (C-terminal binding protein 2) and histone acetyltransferase p300. Our in vitro data demonstrated that induction of CtBP2 by recombinant IL-1β (interleukin-1 beta) led to the upregulation of TGFB1 and the activation of TGF-β downstream signaling, while knockdown of CtBP2 resulted in the reversed effects. Using chromatin immunoprecipitation assays, we revealed that the CtBP2-p300-AP1 complex specifically bound to the promoter of TGFB and that knockdown or blockage of CtBP2 significantly decreased the occupancies of the p300 and AP-1 subunits. Our results support a model in which the CtBP2-p300-AP1 transcriptional complex activates the expression of TGFB1, increasing its production and extracellular secretion. The secreted TGF-β binds to its receptors and initiates downstream signaling.

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“…30 In CKD mice, comorbidity with ischemic stroke significantly increases infarct volume, worsens neurological deficits, and significantly increases inflammatory responses such as increased M1 microglia/macrophage and inflammatory cytokine expression in the ischemic brain. 31 In addition to chronic inflammation, increased oxidative stress, decreased nitric oxide production, endothelial dysfunction, platelet aggregation, and vascular injury may contribute to stroke in CKD patients. 26 The mechanisms underlying CKD induced aggravated stroke pathogenesis, and worse stroke outcomes have been recently reviewed.…”

Section: Epidemiology: Brain and Kidney Interactionmentioning

confidence: 99%

Brain–kidney interaction: Renal dysfunction following ischemic stroke

Zhao

Yan

Chopp

et al. 2019

J Cereb Blood Flow Metab

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Stroke is a leading cause of mortality and morbidity, with long-term debilitating effects. Accumulating evidence from experimental studies as well as observational studies in patients suggests a cross talk between the brain and kidney after stroke. Stroke may lead to kidney dysfunction which can adversely impact patient outcome. In this review article, we discuss the epidemiology and mechanisms of brain–kidney interaction following ischemic stroke. Specifically, we discuss the role of the central autonomic network, autoregulation, inflammatory and immune responses, the role of extracellular vesicles and their cargo microRNA, in mediating brain–kidney interaction following stroke. Understanding the bidirectional nature of interaction between the brain and kidney after cerebral injury would have clinical implications for the treatment of stroke and overall patient outcome.

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Cellular and molecular mechanisms associated with ischemic stroke severity in female mice with chronic kidney disease

Cited by 24 publications

References 41 publications

Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications

Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications

Transforming growth factor beta (TGF-β) is activated by the CtBP2-p300-AP1 transcriptional complex in chronic renal failure

Brain–kidney interaction: Renal dysfunction following ischemic stroke

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