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

• Published in: Chemico-biological interactions Vol. 206; no. 1; pp. 47 - 54
• Main Authors: Gorostizaga, Alejandra, Mori Sequeiros García, Maria Mercedes, Acquier, Andrea, Gomez, Natalia V., Maloberti, Paula M., Mendez, Carlos F., Paz, Cristina
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 25.10.2013
• Subjects: adverse effects; Albumin; albumins; Animals; Cattle; Cells, Cultured; dephosphorylation; Didelphis - metabolism; Dual Specificity Phosphatase 1 - genetics; Dual Specificity Phosphatase 1 - metabolism; endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic reticulum stress; ERK1/2; gene activation; kidney cells; Kidney Tubules, Proximal - cytology; Kidney Tubules, Proximal - metabolism; messenger RNA; mitogen-activated protein kinase; MKPs; OK cells; Oxidative Stress; phosphorylation; renal function; Reverse Transcriptase Polymerase Chain Reaction; Serum Albumin, Bovine - metabolism; stress response; transcription (genetics); Up-Regulation; urine; OK cells; MKPs; GRP78; Albumin; MAPKKs; ER; JNKs; SP600125; Endoplasmic reticulum stress; BSA; CHX; ERK1/2; MKP; Act D; ERKs; UPR; PD98059; SAPKs; OK; MAPK phosphatase; Anthra[1-9-cd]pyrazol-6(2H); c-Jun NH2-terminal protein kinases; MAPK kinases; actinomycin D; extracellular signal-regulated kinases; glucose-regulated protein 78; 2-amino-3-methoxyphenyl)4H-1-benzopyran-4-one; Free fatty acid albumin; cycloheximide; unfolded protein response; stress-activated protein kinases; Opossum kidney; endoplasmic reticulum
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2013.08.009

•Albumin rapidly increases both MKP-1 mRNA and protein levels.•The effect of albumin on MKP-1 mRNA levels is due to gene transcription activation.•Albumin induces MKP-1 protein accumulation promoting its stabilization.•Albumin induces GRP78 mRNA through an ERK-dependent mechanism.•MKP-1 induction downregulates the albumin-induced ER stress marker GRP78. 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 15min of exposure, peaked at 1h (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 1h) 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.