RESUMEN
Chronic 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.
Asunto(s)
Metformina/uso terapéutico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/prevención & control , Adenilato Quinasa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Peso Corporal , Infarto Encefálico/sangre , Infarto Encefálico/complicaciones , Infarto Encefálico/tratamiento farmacológico , Infarto Encefálico/genética , Activación Enzimática/efectos de los fármacos , Femenino , Regulación de la Expresión Génica , Gliosis/sangre , Gliosis/complicaciones , Gliosis/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/sangre , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/genética , Precondicionamiento Isquémico , Macrófagos/efectos de los fármacos , Macrófagos/patología , Metformina/sangre , Metformina/farmacología , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/patología , Modelos Biológicos , FN-kappa B/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/genética , Accidente Cerebrovascular/genéticaRESUMEN
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-1ß, 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.
Asunto(s)
Isquemia Encefálica/fisiopatología , Corteza Renal/metabolismo , Debilidad Muscular/fisiopatología , Neuronas/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Accidente Cerebrovascular/fisiopatología , Adenilato Quinasa/genética , Adenilato Quinasa/metabolismo , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Apoptosis/genética , Isquemia Encefálica/complicaciones , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Modelos Animales de Enfermedad , Electrocoagulación , Femenino , Regulación de la Expresión Génica , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Corteza Renal/patología , Ratones , Ratones Endogámicos C57BL , Debilidad Muscular/complicaciones , Debilidad Muscular/genética , Debilidad Muscular/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Neuroglía/metabolismo , Neuroglía/patología , Neuronas/patología , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismo , Prueba de Desempeño de Rotación con Aceleración Constante , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/metabolismoRESUMEN
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.
