RESUMO
Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in the PKD1 and PKD2 genes, and it is characterized by renal cyst formation, inflammation and fibrosis. Forkhead box protein M1 (FoxM1), a transcription factor of the Forkhead box (Fox) protein super family, has been reported to promote tumor formation, inflammation and fibrosis in many organs. However, the role and mechanism of FoxM1 in regulation of ADPKD progression is still poorly understood. Here, we show that FoxM1 is an important regulator of cyst growth in ADPKD. FoxM1 is upregulated in cyst-lining epithelial cells in Pkd1 mutant mouse kidneys and human ADPKD kidneys. FoxM1 promotes cystic renal epithelial cell proliferation by increasing the expression of Akt and Stat3 and the activation of ERK and Rb. FoxM1 also regulates cystic renal epithelial cell apoptosis through NF-κB signaling pathways. In addition, FoxM1 regulates the recruitment and retention of macrophages in Pkd1 mutant mouse kidneys, a process that is associated with FoxM1-mediated upregulation of monocyte chemotactic protein 1. Targeting FoxM1 with its specific inhibitor, FDI-6, delays cyst growth in rapidly progressing and slowly progressing Pkd1 mutant mouse kidneys. This study suggests that FoxM1 is a central and upstream regulator of ADPKD pathogenesis and provides a rationale for targeting FoxM1 as a therapeutic strategy for ADPKD treatment.
Assuntos
Cistos , Rim Policístico Autossômico Dominante , Animais , Humanos , Camundongos , Proliferação de Células/genética , Cistos/genética , Cistos/patologia , Fibrose , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Inflamação/patologia , Rim/metabolismo , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/patologia , Fatores de Transcrição/metabolismo , Canais de Cátion TRPP/genética , Canais de Cátion TRPP/metabolismoRESUMO
In the CNS, myelination and remyelination depend on the successful progression and maturation of oligodendroglial lineage cells, including proliferation and differentiation of oligodendroglial progenitor cells (OPCs). Previous studies have reported that Sox2 transiently regulates oligodendrocyte (OL) differentiation in the embryonic and perinatal spinal cord and appears dispensable for myelination in the postnatal spinal cord. However, the role of Sox2 in OL development in the brain has yet to be defined. We now report that Sox2 is an essential positive regulator of developmental myelination in the postnatal murine brain of both sexes. Stage-specific paradigms of genetic disruption demonstrated that Sox2 regulated brain myelination by coordinating upstream OPC population supply and downstream OL differentiation. Transcriptomic analyses further supported a crucial role of Sox2 in brain developmental myelination. Consistently, oligodendroglial Sox2-deficient mice developed severe tremors and ataxia, typical phenotypes indicative of hypomyelination, and displayed severe impairment of motor function and prominent deficits of brain OL differentiation and myelination persisting into the later CNS developmental stages. We also found that Sox2 was required for efficient OPC proliferation and expansion and OL regeneration during remyelination in the adult brain and spinal cord. Together, our genetic evidence reveals an essential role of Sox2 in brain myelination and CNS remyelination, and suggests that manipulation of Sox2 and/or Sox2-mediated downstream pathways may be therapeutic in promoting CNS myelin repair.SIGNIFICANCE STATEMENT Promoting myelin formation and repair has translational significance in treating myelin-related neurological disorders, such as periventricular leukomalacia and multiple sclerosis in which brain developmental myelin formation and myelin repair are severely affected, respectively. In this report, analyses of a series of genetic conditional knock-out systems targeting different oligodendrocyte stages reveal a previously unappreciated role of Sox2 in coordinating upstream proliferation and downstream differentiation of oligodendroglial lineage cells in the mouse brain during developmental myelination and CNS remyelination. Our study points to the potential of manipulating Sox2 and its downstream pathways to promote oligodendrocyte regeneration and CNS myelin repair.
Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Sistema Nervoso Central/fisiologia , Bainha de Mielina/fisiologia , Oligodendroglia/fisiologia , Fatores de Transcrição SOXB1/fisiologia , Animais , Diferenciação Celular/fisiologia , Proliferação de Células , Doenças Desmielinizantes/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Transtornos dos Movimentos/fisiopatologia , Regeneração Nervosa/fisiologia , Medula Espinal/crescimento & desenvolvimento , Medula Espinal/fisiologia , TranscriptomaRESUMO
The mechanisms by which oligodendroglia modulate CNS angiogenesis remain elusive. Previous in vitro data suggest that oligodendroglia regulate CNS endothelial cell proliferation and blood vessel formation through hypoxia inducible factor alpha (HIFα)-activated Wnt (but not VEGF) signaling. Using in vivo genetic models, we show that HIFα in oligodendroglia is necessary and sufficient for angiogenesis independent of CNS regions. At the molecular level, HIFα stabilization in oligodendroglia does not perturb Wnt signaling but rather activates VEGF. At the functional level, genetically blocking oligodendroglia-derived VEGF but not Wnt significantly decreases oligodendroglial HIFα-regulated CNS angiogenesis. Blocking astroglia-derived Wnt signaling reduces astroglial HIFα-regulated CNS angiogenesis. Together, our in vivo data demonstrate that oligodendroglial HIFα regulates CNS angiogenesis through Wnt-independent and VEGF-dependent signaling. These findings suggest an alternative mechanistic understanding of CNS angiogenesis by postnatal glial cells and unveil a glial cell type-dependent HIFα-Wnt axis in regulating CNS vessel formation.
Assuntos
Astrócitos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neovascularização Fisiológica , Oligodendroglia/metabolismo , Animais , Animais Recém-Nascidos , Proliferação de Células , Células Cultivadas , Células Endoteliais/metabolismo , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos , Camundongos Knockout , Cultura Primária de Células , Prosencéfalo/irrigação sanguínea , Prosencéfalo/citologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Via de Sinalização Wnt/fisiologiaRESUMO
Levodopa (L-dopa) is the key component in Parkinson's disease (PD) treatment. Recently, we demonstrated that ß-asarone improves the motor behavior of rats with unilateral striatal 6-hydroxydopamine lesion. Striatal level of dopamine (DA) and L-dopa increased after ß-asarone and L-dopa co-administered treatment in healthy rat. Since its effects and mechanisms on PD rats are still unclear, we investigated whether coadministration could help treat PD rats. Here, PD rats were randomly divided into seven groups (n=10/group): an untreated group, a Madopar-treated group, a L-dopa-treated group, a ß-asarone-treated group, and groups receiving low, medium or high doses of ß-asarone respectively plus the same dose of L-dopa. The sham-operated group rats were injected with saline. Treatments were administered to the rats twice per day continuously for 30days. The behavioral tests were assessed. Neurotransmitters, dopa decarboxylase (DDC), tyrosine hydroxylase (TH), catechol-O-methyltransferase (COMT), monoamine oxidase B (MAO-B) and dopamine transporter (DAT) levels were detected. The pathological characteristics of liver and kidney and ultrastructure of dopaminergic neurons were observed. The behavior of PD rats improved significantly after co-administered treatment compared with the untreated group. In addition, our results also showed that co-administered treatment increased L-dopa, DA, DOPAC, HVA and 5-HT levels, enhanced the MAO-B, COMT, TH and DAT levels, reduced creatinine level, decreased the amount of lysosome and mitochondria and showed no liver and kidney toxicity. These findings suggest that co-administered treatment could elevate striatal levels of L-dopa and DA and improve the behavioral abilities in PD rats by regulating the DDC, TH, MAO-B, COMT and DAT levels.
Assuntos
Anisóis/farmacologia , Antiparkinsonianos/farmacologia , Levodopa/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Derivados de Alilbenzenos , Animais , Anisóis/administração & dosagem , Antiparkinsonianos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Benserazida/farmacologia , Catecol O-Metiltransferase/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopa Descarboxilase/metabolismo , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Levodopa/administração & dosagem , Masculino , Oxidopamina/toxicidade , Ratos , Ratos Sprague-DawleyRESUMO
ß-asarone, a major component of Acorus tatarinowii Schott, has positive effects in neurodegeneration disease, however, its effect on the Parkinson's disease (PD) remains unclear. In this study, the effects of ß-asarone on behavioral tests, neurotransmitters, tyrosine hydroxylase (TH), and α-synuclein (α-syn) were investigated in 6-hydroxydopamine (6-OHDA) induced rats. Furthermore, the JNK/Bcl-2/Beclin-1 autophagy pathway was also studied. The results showed that ß-asarone improved the behavioral symptoms of rats in the open field, rotarod test, initiation time, and stepping time. And it increased the HVA, Dopacl, and 5-HIAA levels in striatum but not the DA and 5-HT levels. After administration of ß-asarone, the TH level was elevated but the α-syn was declined in rats. It inhibited the expressions of LC3-II, but increased the p62 expression in SN4741 cells. Moreover, it affected the expressions of Beclin-1, Bcl-2, JNK, and p-JNK in vivo. We deduced that ß-asarone may firstly downregulate expressions of JNK and p-JNK, and then indirectly increase the expression of Bcl-2. And the function of Beclin-1 could be inhibited, which could inhibit autophagy activation. Collectively, all data indicated that ß-asarone may be explored as a potential therapeutic agent in PD therapy.
Assuntos
Anisóis/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopamina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/metabolismo , Derivados de Alilbenzenos , Animais , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/efeitos dos fármacos , Proteína Beclina-1 , Corpo Estriado/metabolismo , Masculino , Oxidopamina/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-DawleyRESUMO
Immediate neurochemical alterations produced by 6-OHDA could explain the general toxic pattern in the central nervous system. However, no evidences describe the effects of 6-OHDA on early changes of neurotransmitters in rats' striatum, cortex and hippocampus. In our study, unilateral 6-OHDA injection into medial forebrain bundle (MFB) was used in rats, then five neurotransmitters were analyzed at 3, 6, 12, 24, 48 and 72 h, respectively. Results showed that 6-OHDA injection caused a sharp decline of striatal dopamine (DA) levels in the first 12h followed by a further reduction between 12 and 48 h. However, striatal levels of homovanillic acid (HVA) were stable in the first 12h and showed a marked reduction between 12 and 24h. Striatal levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) decreased linearly for 72 h, whereas levels of norepinephrine (NE) showed a slight reduction in the first 48 h, and returned back to normal afterwards. Striatal HVA/DA ratio increased significantly in the first 12h, but 5-HIAA/5-HT ratio showed a sharp increase between 12 and 72 h. Besides, neurochemical alterations were also found in hippocampus and cortex, and the correlations of neurotransmitters were analyzed. Our study indicated that NE system had little influence in the early phase of 6-OHDA injection, moreover, early neurochemical alterations were involved with striatum, hippocampus and cortex.