Modulation of albumin-induced endoplasmic reticulum stress in renal proximal tubule cells by upregulation of mapk phosphatase-1

Authors
Gorostizaga, Alejandra Beatriz; Mori Sequeiros, María de Las Mercedes; Acquier, Andrea Beatriz; Gómez, Natalia; Maloberti, Paula Mariana; Mendez, Carlos Fernando; Paz, Cristina del Valle
Publication Year
2013
Language
English
Format
article
Status
Published version
Description
High amounts of albumin in urine cause tubulointerstitial damage that leads to a rapid deterioration of the renal function. Albumin exerts its injurious effects on renal cells through a process named endoplasmic reticulum (ER) stress due to the accumulation of unfolded proteins in the ER lumen. In addition, albumin promotes phosphorylation and consequent activation of MAPKs such as ERK1/2. Since ERK1/2 activation promoted by albumin is a transient event, the aims of the present work were to identify the phosphatase involved in their dephosphorylation in albumin-exposed cells and to analyze the putative regulation of this phosphatase by albumin. We also sought to determine the role played by the phospho/dephosphorylation of ERK1/2 in the cellular response to albumin-induced ER stress. MAP kinase phosphatase-1, MKP-1, is a nuclear enzyme involved in rapid MAPK dephosphorylation. Here we present evidence supporting the notion that this phosphatase is responsible for ERK1/2 dephosphorylation after albumin exposure in OK cells. Moreover, we demonstrate that exposure of OK cells to albumin transiently increases MKP-1 protein levels. The increase was evident after 15 min of exposure, peaked at 1 h (6-fold) and declined thereafter. In cells overexpressing flag-MKP-1, albumin caused the accumulation of this chimera, promoting MKP-1 stabilization by a posttranslational mechanism. Albumin also promoted a transient increase in MKP-1 mRNA levels (3-fold at 1 h) through the activation of gene transcription. In addition, we also show that albumin increased mRNA levels of GRP78, a key marker of ER stress, through an ERK-dependent pathway. In line with this finding, our studies demonstrate that flag-MKP-1 overexpression blunted albumin-induced GRP78 upregulation. Thus, our work demonstrates that albumin overload not only triggers MAPK activation but also tightly upregulates MKP-1 expression, which might modulate ER stress response to albumin overload.
Fil: Gorostizaga, Alejandra Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina
Fil: Mori Sequeiros, María de Las Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina
Fil: Acquier, Andrea Beatriz. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Farmacología; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina; Argentina
Fil: Gómez, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina
Fil: Maloberti, Paula Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina
Fil: Mendez, Carlos Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Farmacología; Argentina
Fil: Paz, Cristina del Valle. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina
Subject
Albumin
OK cells
ERK1/2
MKPs
Endoplasmic reticulum stress
Bioquímica y Biología Molecular
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/15224