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Can J Ophthalmol. 2009 Aug;44(4):431-6. doi: 10.3129/i09-109.

p38 mitogen-activated protein kinase protects human retinal pigment epithelial cells exposed to oxidative stress.

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1
Department of Ophthalmology, University of Western Ontario, London, Ontario, Canada.

Abstract

OBJECTIVE:

To investigate the role of p38 mitogen-activated protein kinase (MAPK) in human retinal pigment epithelial (RPE) cells exposed to acute oxidative stress.

STUDY DESIGN:

Experimental study.

METHODS:

Oxidative stress was induced by the chemical oxidant tert-butyl hydroperoxide (t-BOOH) in the human RPE cell line ARPE-19. Cell viability was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The phosphorylation of p38 MAPK was measured by Western blot analysis. Small interfering (si)RNA and plasmid DNA of a constitutive active mutant of a MAPK kinase (MKK6E) were transfected to knock down and activate p38 MAPK in ARPE-19 cells, respectively.

RESULTS:

t-BOOH induced ARPE-19 cell death in a time- and dose-dependent manner. t-BOOH increased phosphorylation of p38 MAPK. Both inhibition of p38 MAPK with a selective inhibitor SB203580 and knockdown of p38? MAPK with siRNA enhanced t-BOOH-induced ARPE-19 cell death (by 29% and 20%, respectively). Overexpression of MKK6E, a kinase upstream of p38 MAPK, increased phosphorylation of p38 MAPK and attenuated t-BOOH-induced ARPE-19 cell death by 16%. Preconditioning with a low dose of t-BOOH decreased the ARPE-19 cell death induced by a higher dose of t-BOOH by 13%. This protective effect was absent when ARPE-19 cells were pretreated with SB203580 for 1 hour before preconditioning.

CONCLUSIONS:

Under the conditions tested, activation of p38 MAPK protects ARPE-19 cells against oxidant-induced death. Because RPE cells play a key role in retinal homeostasis, this finding may have important implications for retinal disease.

PMID:
19606165
DOI:
10.3129/i09-109
[Indexed for MEDLINE]
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