Nephrol Dial Transplant (2002) 17: 998-1004
© 2002 European Renal Association-European Dialysis and Transplant Association
p38 MAPK phosphorylation and NF-
B activation in human crescentic glomerulonephritis
1 Department of Gastroenterology and Nephrology, and Division of Blood Purification, Graduate School of Medicine, 2 Department of Molecular Oncology, Cancer Research Institute, Kanazawa University, 3 Department of Internal Medicine, Kurobe Municipal Hospital, Kurobe, 4 Department of Internal Medicine, National Kanazawa Hospital, Kanazawa and 5 Department of Molecular Preventive Medicine, The University of Tokyo, Tokyo, Japan.
Background. p38 mitogen-activated protein kinase (p38 MAPK) followed by the activation of NF-
B participates in the intracellular signal transduction and production of cytokines and chemokines. The pathophysiological roles of p38 MAPK and NF-B in human glomerulonephritis, however, remain to be investigated.
Methods. We investigated the phosphorylated p38 MAPK (p-p38 MAPK) and activated NF-B 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-1
, the cognate ligand for CCR5, were determined by enzyme-linked immunosorbent assay.
Results. p-p38 MAPK-positive cells and activated NF-B-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-1 levels. In addition, the number of activated NF-B-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-B-positive cells decreased during glucocorticoid therapy-induced convalescence.
Conclusions. We conclude that the phosphorylation of p38 MAPK associated with the activation of NF-B may be involved in the upregulation of intrarenal MIP-1 and the utilization of CCR5 signalling, which may result in human crescentic glomerulonephritis.
Keywords: CCR5; chemokine receptor; crescentic glomerulonephritis; MIP-1; NF-B; p38 MAPK
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: twada{at}medf.m.kanazawa\|[hyphen]\|u.ac.jp
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