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J. Biol. Chem., Vol. 280, Issue 26, 24396-24403, July 1, 2005
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From the Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec H3A 1A1, Canada
C5b-9-induced glomerular epithelial cell (GEC) injury in vivo (in passive Heymann nephritis) and in culture is associated with damage to the endoplasmic reticulum (ER) and increased expression of ER stress proteins. Induction of ER stress proteins is enhanced via cytosolic phospholipase A2 (cPLA2) and limits complement-dependent cytotoxicity. The present study addresses another aspect of the ER unfolded protein response, i.e. activation of protein kinase R-like ER kinase (PERK or pancreatic ER kinase), which phosphorylates eukaryotic translation initiation factor 2-
(eIF2), thereby generally suppressing translation and decreasing the protein load on a damaged ER. Phosphorylation of eIF2 was enhanced significantly in glomeruli of proteinuric rats with passive Heymann nephritis, compared with control. In cultured GECs, complement induced phosphorylation of eIF2 and reduced protein synthesis, and complement-stimulated phosphorylation of eIF2 was enhanced by overexpression of cPLA2. Ischemia-reperfusion in vitro (deoxyglucose plus antimycin A followed by glucose re-exposure) also stimulated eIF2 phosphorylation and reduced protein synthesis. Complement and ischemia-reperfusion induced phosphorylation of PERK (which correlates with activation), and fibroblasts from PERK knock-out mice were more susceptible to complement- and ischemia-reperfusion-mediated cytotoxicity, as compared with wild type fibroblasts. The GEC protein, nephrin, plays a key role in maintaining glomerular permselectivity. In contrast to a general reduction in protein synthesis, translation regulated by the 5'-end of mouse nephrin mRNA during ER stress was paradoxically maintained, probably due to the presence of short open reading frames in this mRNA segment. Thus, phosphorylation of eIF2 and consequent general reduction in protein synthesis may be a novel mechanism for limiting complement- or ischemia-reperfusion-dependent GEC injury.
Received for publication, January 20, 2005 , and in revised form, April 27, 2005.
* This work was supported in part by Research Grants from the Canadian Institutes of Health Research and the Kidney Foundation of Canada. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Both authors hold scholarships from the Fonds de la Recherche en Santé du Québec.
¶ Awarded a fellowship from the McGill University Health Centre Research Institute.
To whom correspondence should be addressed: Division of Nephrology, Royal Victoria Hospital, 687 Pine Ave. West, Montreal, Quebec H3A 1A1, Canada. Tel.: 514-398-8148; Fax: 514-843-2815; E-mail: andrey.cybulsky{at}mcgill.ca.
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