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This Article Full Text Full Text (PDF) web only appendix All Versions of this Article: ard.2007.077263v1 ard.2007.077263v2 67/5/602    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this link to a friend Similar articles in this journal Similar articles in PubMed Add article to my folders Download to citation manager Request Permissions Google Scholar Articles by Polzer, K Articles by Zwerina, J PubMed PubMed Citation Articles by Polzer, K Articles by Zwerina, J

Selective p38MAPK isoform expression and activation in antineutrophil cytoplasmatic antibody-associated crescentic glomerulonephritis: role of p38MAPK

¹ Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen, Germany
² Department of Clinical Pathology, Medical University of Vienna, Austria
³ Department of Internal Medicine 3, Medical University of Vienna, Austria

Correspondence to:
Jochen Zwerina, MD, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany; jochen.zwerina{at}uk-erlangen.de

Objective: Crescentic glomerulonephritis (crGN) is a frequent and life-threatening manifestation of antineutrophil cytoplasmatic antibody-associated vasculitis. Up-regulation of proinflammatory cytokines contributes to renal damage by activation of p38 mitogen-activated protein kinases (MAPKs). However, it is unclear which of the four p38MAPK isoforms are expressed, activated and hence of major importance in crGN.

Methods: Kidney biopsies of patients with antineutrophil cytoplasmatic antibody-positive crGN and control samples were investigated for the expression and phosphorylation of p38MAPK isoforms and downstream target kinase MAPKAP2 by immunohistochemistry. Expression and functional activation of p38MAPK isoforms by TNF was also assessed in a human podocyte cell line by reverse transcription–polymerase chain reaction, immunoblotting and kinase array.

Results: Strong expression of p38MAPK, β and isoforms was found in glomerular podocytes and crescents. Infiltrating leucocytes showed predominant p38MAPK expression. Activation of p38MAPK and its downstream mediator MAPKAP2 was found in crGN confined to glomerular podocytes, crescents and inflammatory infiltrates. Interestingly, corticosteroid treatment before kidney biopsy diminished p38MAPK activation in crGN. Activated p38MAPK co-localised with , β and isoforms in podocytes and crescents, while leucocytes showed mainly p38MAPK activation. In a human podocyte cell line mRNA and protein of all four p38MAPK isoforms was expressed but only p38MAPK was activated upon challenge with TNF.

Conclusions: This study shows selective p38MAPK isoform expression and activation in crGN. Podocytes and podocyte-induce crescent formation is the main source of p38MAPK activation in crGN. TNF is a potent and selective activator of the -isoform in podocytes, which therefore appears as a main contributor to proinflammatory signalling in the glomerulum of crGN.