Impact de l'insuffisance rénale chronique sur la sévérité des accidents vasculaires cérébraux dans un modèle de souris : rôle de l'adénosine monophosphate-activated protein kinase, AMPK

Stroke is the third cause of cardiovascular death in patients suffering from chronic kidney disease (CKD). In these patients, stroke is associated with more severe neurological deterioration, poorer functional recovery, and increased mortality. To date, the processes by which CKD worsens the severity of ischemic stroke are not fully understood and therapeutic strategies aiming to prevent stroke severity in these patients are missing. This work aimed to investigate the cellular and molecular mechanism associated with ischemic stroke severity in an in vivo model of CKD. To this end, a 15-minute transient ischemic stroke was induced by middle cerebral artery occlusion in female C57BL6J mice suffering or not from CKD. Ischemic lesions and motor impairment were more severe in CKD than in control mice. Ischemic lesions from CKD mice were also more inflammatory and showed reduced phosphorylation of the adenosine monophosphate-activated protein kinase (AMPK) compared to those of control mice. AMPK is a protein whose activation is known to reduce the pro-inflammatory M1 polarisation of microglia/macrophages. Therefore, we hypothesized that the increased inflammation observed within the ischemic hemispheres of CKD mice was due to the decrease of AMPK activity. Confirming this hypothesis, reactivation of AMPK by metformin treatment reduced ischemic volumes, inflammation and motor impairments in CKD mice. These data suggest that metformin may be of interest in preventing the severity of stroke in CKD patientsL'accident vasculaire cérébral (AVC) est la 3ème cause de mortalité par maladies cardiovasculaires chez les patients atteints d'insuffisance rénale chronique (IRC). Chez ces patients, les troubles cognitifs et moteurs consécutifs à l'AVC sont plus sévères et associés à un plus mauvais pronostic qu'en population générale. Les mécanismes par lesquels l'IRC aggrave la sévérité des AVC n'ont pas encore été élucidés. Le premier objectif du travail était de mettre au point un modèle murin permettant d'étudier les mécanismes cellulaires et moléculaires associés à la sévérité de l'AVC dans l'IRC. Pour cela, nous avons provoqué un AVC ischémique transitoire de 15 minutes par occlusion de l'artère cérébrale moyenne chez des souris C57BL6J femelles souffrant ou non d'une IRC. Dans notre modèle, la sévérité des atteintes ischémiques et motrices des souris IRC était associée à une élévation de l'inflammation et à une réduction de la phosphorylation de l'adenosine monophosphate-activated protein kinase (AMPK) au sein des zones lésionnelles. L'AMPK est une protéine dont l'activation réduit la polarisation M1 pro-inflammatoire des microglies/macrophages. Nous avons donc émis l'hypothèse que la forte inflammation observée dans les hémisphères ischémiés des souris IRC pouvait être liée à la baisse d'activité AMPK. Confirmant cette hypothèse, dans notre modèle la réactivation de l'AMPK grâce à un traitement par la metformine a permis de réduire le volume d'ischémie cérébrale, l'inflammation ainsi que les atteintes motrices des souris IRC. Ces données suggèrent que la metformine pourrait avoir un intérêt dans la prévention de la sévérité des AVC chez les patients atteints d'IR

Impact of chronic kidney disease on stroke severity in mice : role of adenosine monophosphate-activated protein kinase

L'accident vasculaire cérébral (AVC) est la 3ème cause de mortalité par maladies cardiovasculaires chez les patients atteints d'insuffisance rénale chronique (IRC). Chez ces patients, les troubles cognitifs et moteurs consécutifs à l'AVC sont plus sévères et associés à un plus mauvais pronostic qu'en population générale. Les mécanismes par lesquels l'IRC aggrave la sévérité des AVC n'ont pas encore été élucidés. Le premier objectif du travail était de mettre au point un modèle murin permettant d'étudier les mécanismes cellulaires et moléculaires associés à la sévérité de l'AVC dans l'IRC. Pour cela, nous avons provoqué un AVC ischémique transitoire de 15 minutes par occlusion de l'artère cérébrale moyenne chez des souris C57BL6J femelles souffrant ou non d'une IRC. Dans notre modèle, la sévérité des atteintes ischémiques et motrices des souris IRC était associée à une élévation de l'inflammation et à une réduction de la phosphorylation de l'adenosine monophosphate-activated protein kinase (AMPK) au sein des zones lésionnelles. L'AMPK est une protéine dont l'activation réduit la polarisation M1 pro-inflammatoire des microglies/macrophages. Nous avons donc émis l'hypothèse que la forte inflammation observée dans les hémisphères ischémiés des souris IRC pouvait être liée à la baisse d'activité AMPK. Confirmant cette hypothèse, dans notre modèle la réactivation de l'AMPK grâce à un traitement par la metformine a permis de réduire le volume d'ischémie cérébrale, l'inflammation ainsi que les atteintes motrices des souris IRC. Ces données suggèrent que la metformine pourrait avoir un intérêt dans la prévention de la sévérité des AVC chez les patients atteints d'IRCStroke is the third cause of cardiovascular death in patients suffering from chronic kidney disease (CKD). In these patients, stroke is associated with more severe neurological deterioration, poorer functional recovery, and increased mortality. To date, the processes by which CKD worsens the severity of ischemic stroke are not fully understood and therapeutic strategies aiming to prevent stroke severity in these patients are missing. This work aimed to investigate the cellular and molecular mechanism associated with ischemic stroke severity in an in vivo model of CKD. To this end, a 15-minute transient ischemic stroke was induced by middle cerebral artery occlusion in female C57BL6J mice suffering or not from CKD. Ischemic lesions and motor impairment were more severe in CKD than in control mice. Ischemic lesions from CKD mice were also more inflammatory and showed reduced phosphorylation of the adenosine monophosphate-activated protein kinase (AMPK) compared to those of control mice. AMPK is a protein whose activation is known to reduce the pro-inflammatory M1 polarisation of microglia/macrophages. Therefore, we hypothesized that the increased inflammation observed within the ischemic hemispheres of CKD mice was due to the decrease of AMPK activity. Confirming this hypothesis, reactivation of AMPK by metformin treatment reduced ischemic volumes, inflammation and motor impairments in CKD mice. These data suggest that metformin may be of interest in preventing the severity of stroke in CKD patient

CHRONIC RENAL FAILURE WORSENS ISCHEMIC STROKE SIZE AND ALTERS NEUROLOGICAL FUNCTIONS IN MICE

International audienc

The Impact of Uremic Toxins on Cerebrovascular and Cognitive Disorders

Individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing cognitive disorders and dementia. Stroke is also highly prevalent in this population and is associated with a higher risk of neurological deterioration, in-hospital mortality, and poor functional outcomes. Evidence from in vitro studies and in vivo animal experiments suggests that accumulation of uremic toxins may contribute to the pathogenesis of stroke and amplify vascular damage, leading to cognitive disorders and dementia. This review summarizes current evidence on the mechanisms by which uremic toxins may favour the occurrence of cerebrovascular diseases and neurological complications in CKD

New Insights into the Roles of Monocytes/Macrophages in Cardiovascular Calcification Associated with Chronic Kidney Disease

International audienceCardiovascular disease (CVD) is an important cause of death in patients with chronic kidney disease (CKD), and cardiovascular calcification (CVC) is one of the strongest predictors of CVD in this population. Cardiovascular calcification results from complex cellular interactions involving the endothelium, vascular/valvular cells (i.e., vascular smooth muscle cells, valvular interstitial cells and resident fibroblasts), and monocyte-derived macrophages. Indeed, the production of pro-inflammatory cytokines and oxidative stress by monocyte-derived macrophages is responsible for the osteogenic transformation and mineralization of vascular/valvular cells. However, monocytes/macrophages show the ability to modify their phenotype, and consequently their functions, when facing environmental modifications. This plasticity complicates efforts to understand the pathogenesis of CVC-particularly in a CKD setting, where both uraemic toxins and CKD treatment may affect monocyte/macrophage functions and thereby influence CVC. Here, we review (i) the mechanisms by which each monocyte/macrophage subset either promotes or prevents CVC, and (ii) how both uraemic toxins and CKD therapies might affect these monocyte/macrophage functions

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

Abstract Ischemic stroke is highly prevalent in chronic kidney disease (CKD) patients and has been associated with a higher risk of neurological deterioration and in-hospital mortality. To date, little is known about the processes by which CKD worsens ischemic stroke. This work aimed to investigate the cellular and molecular mechanism associated with ischemic stroke severity in an in vivo model of CKD. CKD was induced through right kidney cortical electrocautery in 8-week-old female C57BL/6 J mice followed by left total nephrectomy. Transient middle cerebral artery occlusion (tMCAO) was performed 6 weeks after left nephrectomy. Twenty-four hours after tMCAO, the infarct volumes were significantly wider in CKD than in SHAM mice. CKD mice displayed decreased neuroscore, impaired ability to remain on rotarod device, weaker muscular strength and decreased prehensile score. Apoptosis, neuronal loss, glial cells recruitment and microglia/macrophages M1 signature genes CD32, CD86, IL-1β, IL-6, MCP1 and iNOS were significantly increased within ischemic lesions of CKD mice. This effect was associated with decreased AMP kinase phosphorylation and increased activation of the NFΚB pathway. Pharmacological targeting of AMP kinase activity, which is known to block microglia/macrophages M1 polarization, appears promising to improve stroke recovery in CKD

Metformin alleviates stroke severity in female mice with chronic kidney disease through AMPK activation and subsequent decrease of microglia/macrophages M1 polarization

56th Congress of the European-Renal-Association (ERA)-European-Dialysis-and-Transplant-Association (EDTA) - Burden, Access and Disparities in Kidney Disease, Budapest, HUNGARY, JUN 13-16, 2019International audienc

Metformin prevents stroke damage in non-diabetic female mice with chronic kidney disease

International audienceChronic kidney disease (CKD) worsens ischemic stroke severity in both patients and animals. In mice, these poorer functional outcomes are associated with decreased brain activity of AMP-activated protein kinase (AMPK), a molecule that recently emerged as a potential therapeutic target for ischemic stroke. The antidiabetic drug metformin, a well-known activator of AMPK, has improved stroke outcomes in diabetic patients with normal renal function. We investigated whether chronic metformin pre-conditioning can rescue AMPK activity and prevent stroke damage in non-diabetic mice with CKD. Eight-week-old female C57BL/6J mice were assigned to CKD or SHAM groups. CKD was induced through right kidney cortical electrocautery, followed by left total nephrectomy. Mice were then allocated to receive metformin (200 mg/kg/day) or vehicle for 5 weeks until stroke induction by transient middle cerebral artery occlusion (tMCAO). The infarct volumes were lower in CKD mice exposed to metformin than in vehicle-treated CKD mice 24 h after tMCAO. Metformin pre-conditioning of CKD mice improved their neurological score, grip strength, and prehensile abilities. It also enhanced AMPK activation, reduced apoptosis, increased neuron survival and decreased microglia/macrophage M1 signature gene expression as well as CKD-induced activation of the canonical NF-κB pathway in the ischemic lesions of CKD mice