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High-mobility group box-1 protein promotes granulomatous nephritis in adenine-induced nephropathy

Academic Article
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Overview

authors

  • Oyama, Y.
  • Hashiguchi, T.
  • Taniguchi, N.
  • Tancharoen, S.
  • Uchimura, T.
  • Biswas, K. K.
  • Kawahara, K.
  • Nitanda, T.
  • Umekita, Y.
  • Lotz, Martin
  • Maruyama, I.

publication date

  • June 2010

journal

  • Laboratory Investigation  Journal

abstract

  • Granulomatous nephritis can be triggered by diverse factors and results in kidney failure. However, despite accumulating data about granulomatous inflammation, pathogenetic mechanisms in nephritis remain unclear. The DNA-binding high-mobility group box-1 protein (HMGB1) initiates and propagates inflammation when released by activated macrophages, and functions as an 'alarm cytokine' signaling tissue damage. In this study, we showed elevated HMGB1 expression in renal granulomas in rats with crystal-induced granulomatous nephritis caused by feeding an adenine-rich diet. HMGB1 levels were also raised in urine and serum, as well as in monocyte chemoattractant protein-1 (MCP-1), a mediator of granulomatous inflammation. Injection of HMGB1 worsened renal function and upregulated MCP-1 in rats with crystal-induced granulomatous nephritis. HMGB1 also induced MCP-1 secretion through mitogen-activated protein kinase (MAPK) and phosphoinositide-3-kinase (PI3K) pathways in rat renal tubular epithelial cells in vitro. Hmgb1(+/-) mice with crystal-induced nephritis displayed reduced MCP-1 expression in the kidneys and in urine and the number of macrophages in the kidneys was significantly decreased. We conclude that HMGB1 is a new mediator involved in crystal-induced nephritis that amplifies granulomatous inflammation in a cycle where MCP-1 attracts activated macrophages, resulting in excessive and sustained HMGB1 release. HMGB1 could be a novel target for inhibiting chronic granulomatous diseases.

subject areas

  • Adenine
  • Animals
  • Blood Urea Nitrogen
  • Chemokine CCL2
  • Creatinine
  • Epithelial Cells
  • Granuloma
  • HMGB1 Protein
  • Inflammation
  • Kidney Diseases
  • Kidney Tubules
  • Mice
  • Nephritis
  • Phosphatidylinositol 3-Kinases
  • Rats
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Research

keywords

  • HMGB1
  • MCP-1
  • chronic inflammation
  • granulomatous nephritis
  • macrophages
  • renal tubular epithelial cells
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Identity

PubMed Central ID

  • PMC3096665

International Standard Serial Number (ISSN)

  • 0023-6837

Digital Object Identifier (DOI)

  • 10.1038/labinvest.2010.64

PubMed ID

  • 20231821
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Additional Document Info

start page

  • 853

end page

  • 866

volume

  • 90

issue

  • 6

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