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1.
Kidney Research and Clinical Practice ; : 329-341, 2017.
Artículo en Inglés | WPRIM | ID: wpr-143318

RESUMEN

BACKGROUND: Soluble epoxide hydrolase (sEH) expressed by endothelial cells catalyzes the metabolism of epoxyeicosatrienoic acids (EETs), which are vasoactive agents. METHODS: We used a unilateral ureteral obstruction mouse model of kidney fibrosis to determine whether inhibition of sEH activity reduces fibrosis, the final common pathway for chronic kidney disease. RESULTS: sEH activity was inhibited by continuous release of the inhibitor 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA) for 1 or 2 weeks. Treatment with AUDA significantly ameliorated tubulointerstitial fibrosis by reducing fibroblast mobilization and enhancing endothelial cell activity. In an in vitro model of endothelial-to-mesenchymal transition (EndMT) using human vascular endothelial cells (HUVECs), AUDA prevented the morphologic changes associated with EndMT and reduced expression of fibroblast-specific protein 1. Furthermore, HUVECs activated by AUDA prevented the epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells in a co-culture system. CONCLUSION: Our findings suggest that regulation of sEH is a potential target for therapies aimed at delaying the progression of kidney fibrosis by inhibiting EndMT and EMT.


Asunto(s)
Animales , Humanos , Ratones , Técnicas de Cocultivo , Células Endoteliales , Células Epiteliales , Transición Epitelial-Mesenquimal , Fibroblastos , Fibrosis , Técnicas In Vitro , Riñón , Metabolismo , Insuficiencia Renal Crónica , Obstrucción Ureteral
2.
Kidney Research and Clinical Practice ; : 329-341, 2017.
Artículo en Inglés | WPRIM | ID: wpr-143311

RESUMEN

BACKGROUND: Soluble epoxide hydrolase (sEH) expressed by endothelial cells catalyzes the metabolism of epoxyeicosatrienoic acids (EETs), which are vasoactive agents. METHODS: We used a unilateral ureteral obstruction mouse model of kidney fibrosis to determine whether inhibition of sEH activity reduces fibrosis, the final common pathway for chronic kidney disease. RESULTS: sEH activity was inhibited by continuous release of the inhibitor 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA) for 1 or 2 weeks. Treatment with AUDA significantly ameliorated tubulointerstitial fibrosis by reducing fibroblast mobilization and enhancing endothelial cell activity. In an in vitro model of endothelial-to-mesenchymal transition (EndMT) using human vascular endothelial cells (HUVECs), AUDA prevented the morphologic changes associated with EndMT and reduced expression of fibroblast-specific protein 1. Furthermore, HUVECs activated by AUDA prevented the epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells in a co-culture system. CONCLUSION: Our findings suggest that regulation of sEH is a potential target for therapies aimed at delaying the progression of kidney fibrosis by inhibiting EndMT and EMT.


Asunto(s)
Animales , Humanos , Ratones , Técnicas de Cocultivo , Células Endoteliales , Células Epiteliales , Transición Epitelial-Mesenquimal , Fibroblastos , Fibrosis , Técnicas In Vitro , Riñón , Metabolismo , Insuficiencia Renal Crónica , Obstrucción Ureteral
3.
Immune Network ; : 257-263, 2013.
Artículo en Inglés | WPRIM | ID: wpr-83832

RESUMEN

Although pathogenesis of human rheumatoid arthritis (RA) remains unclear, arthritogenic T cells and downstream signaling mediators have been shown to play critical roles. An increasing numbers of therapeutic options have been added for the effective control of RA. Nevertheless, there is still a category of patients that fails treatment and suffers from progressive disease. The recently developed immunosuppressant CP-690550, a small molecule JAK kinase inhibitor, has been implicated as an important candidate treatment modality for autoimmune arthritis. In this study, we evaluated the therapeutic effect of CP-690550 on established arthritis using an SKG arthritis model, a pathophysiologically relevant animal model for human RA. CP-690550 treatment revealed remarkable long-term suppressive effects on SKG arthritis when administered to the well-advanced disease (clinical score 3.5~4.0). The treatment effect lasted at least 3 more weeks after cessation of drug infusion, and suppression of disease was correlated with the reduced pro-inflammatory cytokines, including IL-17, IFN-gamma, and IL-6 and increased level of immunoregulatory IL-10.


Asunto(s)
Humanos , Artritis , Artritis Reumatoide , Citocinas , Interleucina-10 , Interleucina-17 , Interleucina-6 , Modelos Animales , Fosfotransferasas , Linfocitos T
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