title: Microparticles released by vascular endothelial cells increase hypoxia inducible factor expression in human proximal tubular HK-2 cells.
abstract: Microparticles are produced by vesiculation of the cell plasma membrane and serve as vectors of cell-to-cell communication. Co-culture experiments have shown that hypoxia-inducible factor-α (HIF-α)-regulated-genes are up-regulated in human renal proximal tubular HK-2 cells by endothelial cell factors which might be transported inside endothelial microparticles (EMP). Here we aimed to study in HK-2 cells the effect of EMP, produced by activated endothelial cells, on HIF-α and HIF-α-regulated vascular endothelial growth factor-A (VEGF-A). EMP, at a concentration much lower than that found in plasma, increased the expression of HIF-α/VEGF-A in a COX-2/EP2 receptor dependent manner. Since the EMP/cells ratio was ∼1/1000, we hypothesized that paracrine mediators produced by HK-2 cells amplified the initial signal. This hypothesis was confirmed by two facts which also suggested that the mediators were conveyed by particles released by HK-2 cells: (i) HIF-α was up-regulated in HK-2 cells treated with the pellet obtained from the conditioned medium of the EMP-treated HK-2 cells. (ii) In transwell experiments, EMP-treated cells increased the expression of HIF-α in untreated HK-2 cells. Interestingly, we detected these cells, particles that were released by EMP-treated HK-2 cells. Depending on the pathological context, activation of HIF-α and VEGF-A signaling in renal tissue/cells may have either beneficial or harmful effects. Therefore, our results suggest that their presence in the urinary space of EMP produced by activated endothelial cells may influence the outcome of a number of renal diseases.
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain. Electronic address: anab.fernandez@uah.es.
authors.forename: Ana Belen
authors.initials: AB
authors.lastname: Fernandez-Martínez
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
authors.forename: Ana Valdehita
authors.initials: AV
authors.lastname: Torija
authors.affiliation: RETICs Red Renal (Instituto de Salud Carlos III), Avda Monforte de Lemos n° 5, 28029 Madrid, Spain; Nephrology Unit, Reina Sofía University Hospital, Avda Menéndez Pidal s/n, 14004 Córdoba, Spain; Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Reina Sofía University Hospital, Avda Menéndez Pidal s/n, 14004 Córdoba, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Carracedo
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain; RETICs Red Renal (Instituto de Salud Carlos III), Avda Monforte de Lemos n° 5, 28029 Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Ramirez
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: de Lucio-Cazaña
mesh_terms: D002450:Cell Communication / Q000235:genetics; D055252:Cell-Derived Microparticles; D051546:Cyclooxygenase 2 / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: Endothelial microparticles; Hypoxia-inducible factor-α; Prostaglandin E2; Proximal tubular cells; Vascular endothelial growth factor-A