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Selective p38MAPK isoform expression and activation in antineutrophil cytoplasmatic antibody-associated crescentic

K Polzer1, A Soleiman, W Baum

  • 1Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen, Erlangen, Germany.

Annals of the Rheumatic Diseases
|August 21, 2007
PubMed

Insights

p38MAPK activation in crescentic glomerulonephritis (crGN) is mainly driven by podocytes, with p38MAPKalpha being selectively activated by TNF. Corticosteroids reduce this activation, offering therapeutic insights for this severe kidney disease.

Area of Science:

  • Nephrology
  • Immunology
  • Molecular Biology

Background:

  • Crescentic glomerulonephritis (crGN) is a severe kidney disease often linked to antineutrophil cytoplasmatic antibody-associated vasculitis.
  • Proinflammatory cytokines and p38 mitogen-activated protein kinases (MAPKs) are implicated in crGN pathogenesis, but specific isoform roles remain unclear.

Purpose of the Study:

  • To investigate the expression, activation, and significance of p38MAPK isoforms in human crGN kidney biopsies.
  • To identify the cellular sources and upstream activators of p38MAPK signaling in crGN.

Main Methods:

  • Immunohistochemistry on kidney biopsies from crGN patients and controls to detect p38MAPK isoforms and MAPKAP2.
  • In vitro studies using a human podocyte cell line to assess p38MAPK isoform expression and activation by TNF via RT-PCR, immunoblotting, and kinase arrays.

Main Results:

  • p38MAPKalpha, beta, and gamma isoforms were expressed in podocytes and crescents in crGN kidneys; p38MAPKalpha predominated in infiltrating leukocytes.
  • Activated p38MAPK and MAPKAP2 were localized to podocytes, crescents, and inflammatory infiltrates, with reduced activation in patients pre-treated with corticosteroids.
  • In vitro, TNF selectively activated p38MAPKalpha in podocytes, despite expression of all four isoforms.

Conclusions:

  • p38MAPK activation in crGN is selective for specific isoforms and primarily originates from podocytes, driving crescent formation.
  • p38MAPKalpha, activated by TNF in podocytes, is a key contributor to inflammation in the glomerulus during crGN.
  • These findings suggest p38MAPKalpha as a potential therapeutic target in crGN.
Abstract

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