MODULATION OF ALBUMIN-INDUCED ENDOPLASMIC RETICULUM STRESS IN RENAL PROXIMAL TUBULE CELLS BY UPREGULATION OF MAPK PHOSPHATASE-1

GOROSTIZAGA AB; MORI SEQUEIROS GARCÍA MM; ACQUIER AB; GOMEZ NV; MALOBERTI PM; MENDEZ CF; PAZ C

CHEMICO-BIOLOGICAL INTERACTIONS

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2013 vol. 206 p. 47 - 54

0009-2797

High amounts of albumin in urine cause tubulointerstitial damage that leads to a rapiddeterioration of the renal function. Albumin exerts its injurious effects on renal cells through aprocess named endoplasmic reticulum (ER) stress due to the accumulation of unfolded proteinsin the ER lumen. In addition, albumin promotes phosphorylation and consequent activation ofMAPKs 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 theirdephosphorylation in albumin-exposed cells and to analyze the putative regulation of thisphosphatase by albumin. We also sought to determine the role played by thephospho/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 MAPKdephosphorylation. Here we present evidence supporting the notion that this phosphatase isresponsible for ERK1/2 dephosphorylation after albumin exposure in OK cells. Moreover, wedemonstrate that exposure of OK cells to albumin transiently increases MKP-1 protein levels.The increase was evident after 15 minutes of exposure, peaked at 1h (6-fold) and declinedthereafter. In cells overexpressing flag-MKP-1, albumin caused the accumulation of thischimera, promoting MKP-1 stabilization by a posttranslational mechanism. Albumin alsopromoted a transient increase in MKP-1 mRNA levels (3-fold at 1 h) through the activation ofgene transcription. In addition, we also show that albumin increased mRNA levels of GRP78, akey marker of ER stress, through an ERK-dependent pathway. In line with this finding, ourstudies demonstrate that flag-MKP-1 overexpression blunted albumin-induced GRP78upregulation. Thus, our work demonstrates that albumin overload not only triggers MAPKactivation but also tightly upregulates MKP-1 expression, which might modulate ER stressresponse to albumin overload.