p38 MAPK phosphorylation and NF-κB activation in human crescentic glomerulonephritis

  • Sakai, Norihiko
  • Wada, Takashi
  • Furuichi, Kengo
  • Iwata, Yasunori
  • Yoshimoto, Keiichi
  • Kitagawa, Kiyoki
  • Kokubo, Satoshi
  • Kobayashi, Motoo
  • Takeda, Shin-ichi
  • Kida, Hiroshi
  • Kobayashi, Ken-ichi
  • Mukaida, Naofumi
  • Matsushima, Kouji
  • Yokoyama, Hitoshi

  • 1Department of Gastroenterology and Nephrology, and Division of Blood Purification, Graduate School of Medicine, Kanazawa University, Kurobe, Japan

    2Department of Molecular Oncology, Cancer Research Institute, Kanazawa University, Kurobe, Japan

    3Department of Internal Medicine, Kurobe Municipal Hospital, Kurobe, Japan

    4Department of Internal Medicine, National Kanazawa Hospital, Kanazawa, Japan

    5Department of Molecular Preventive Medicine, The University of Tokyo, Tokyo, Japan

Correspondence and offprint requests to: Dr Takashi Wada, Department of Gastroenterology and Nephrology, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa 920-8641, Japan. Email: [email protected]

Received for publication: 28.6.01

Accepted in revised form: 10.1.02

Nephrology Dialysis Transplantation 17(6):p 998-1004, June 2002.

Background

p38 mitogen-activated protein kinase (p38 MAPK) followed by the activation of NF-κB participates in the intracellular signal transduction and production of cytokines and chemokines. The pathophysiological roles of p38 MAPK and NF-κB in human glomerulonephritis, however, remain to be investigated.

Methods

We investigated the phosphorylated p38 MAPK (p-p38 MAPK) and activated NF-κB immunohistochemically in the kidneys of 34 patients with crescentic glomerulonephritis and 26 control patients with thin basement membrane disease and minimal change nephrotic syndrome. We also explored the co-localization of p-p38 MAPK with CCR5, the signal of which leads to p38 MAPK activation. Furthermore, urinary levels of MIP-1α, the cognate ligand for CCR5, were determined by enzyme-linked immunosorbent assay.

Results

p-p38 MAPK-positive cells and activated NF-κB-positive cells were mainly detected in crescentic lesions, tubular epithelial cells, and interstitial mononuclear infiltrates. The number of p-p38 MAPK-positive cells in patients with crescentic glomerulonephritis was higher than that in control patients. The number of p-p38 MAPK-positive cells in glomeruli was well correlated with the percentage of cellular crescents, the number of CD68-positive cells, and urinary MIP-1α levels. In addition, the number of activated NF-κB-positive cells was well correlated with the number of p-p38 MAPK-positive cells in glomeruli. Dual staining revealed that most of CCR5-positive cells were positive for p-p38 MAPK. Finally, p-p38 MAPK-positive cells and activated NF-κB-positive cells decreased during glucocorticoid therapy-induced convalescence.

Conclusions

We conclude that the phosphorylation of p38 MAPK associated with the activation of NF-κB may be involved in the upregulation of intrarenal MIP-1α and the utilization of CCR5 signalling, which may result in human crescentic glomerulonephritis.

Copyright © Copyright Oxford University Press 2002.