RESUMEN
Context: Angiopoietin-like protein 2 (ANGPTL2) is a circulating, proinflammatory protein. Objective: To examine the role of ANGPTL2 in the pathogenesis of diabetic kidney disease (DKD), we studied the epigenetic regulation of angptl2 expression in patients with diabetes. Design, Setting, Participants, and Intervention: We determined the relationship between serum ANGPTL2 levels and the progression of DKD in cross-sectional (220 patients) and cohort (145 patients, 7-year follow-up) studies. Furthermore, we investigated the direct effect of ANGPTL2 on podocyte function. Main Outcomes: The main outcome was progression of DKD. Results: We found that the expression of angptl2 was decreased by the methylation of its promoter region. Multivariate logistic regression analyses revealed that the baseline level of serum ANGPTL2 was an independent risk factor for the progression of DKD during follow-up periods. In cultured podocytes, ANGPTL2 directly increased albumin permeability through the translocation of zonula occludens-1 from the membrane to the cytosol via activation of focal adhesion kinase. Conclusions: ANGPTL2 might be directly involved in podocyte dysfunction and independently associated with the progression of DKD stages.
Asunto(s)
Proteínas Similares a la Angiopoyetina/genética , Proteínas Similares a la Angiopoyetina/metabolismo , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Proteína 2 Similar a la Angiopoyetina , Células Cultivadas , Estudios de Cohortes , Estudios Transversales , Nefropatías Diabéticas/patología , Epigénesis Genética , Femenino , Quinasa 1 de Adhesión Focal/metabolismo , Estudios de Seguimiento , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Podocitos/patología , Regiones Promotoras Genéticas , Estudios Retrospectivos , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
Proteins belonging to the Tel2/Rad-5/Clk-2 family are conserved among eukaryotes and are involved in various cellular processes, such as cell proliferation, telomere maintenance, the biological clock, and the DNA damage checkpoint. However, the molecular mechanisms underlying the functions of these molecules remain largely unclear. Here we report that in the fission yeast, Schizosaccharomyces pombe, Tel2 is required for efficient phosphorylation of Mrc1, a mediator of DNA replication checkpoint signaling, and for activation of Cds1, a replication checkpoint kinase, when DNA replication is blocked by hydroxyurea. In fact, Tel2 is required for survival of replication fork arrest and for the replication checkpoint in cells lacking Chk1, another checkpoint kinase the role of which overlaps that of Cds1 in cell cycle arrest by replication block. In addition, Tel2 plays important roles in entry into S phase and in genome stability. Tel2 is essential for vegetative cell growth, and the tel2Delta strain accumulated cells with 1C DNA content after germination. In the absence of hydroxyurea, Tel2 is vital in the mutant lacking Swi1, a component of the replication fork protection complex, and multiple Rad22 DNA repair foci were frequently observed in Tel2-repressed swi1Delta cells especially at S phase. In contrast, the cds1Deltaswi1Delta mutant did not show such lethality. These results indicate that S. pombe Tel2 plays important roles in the Mrc1-mediated replication checkpoint as well as in the Cds1-independent regulation of genome integrity.
