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

Background. p38 mitogen-activated protein kinase (p38 MAPK) followed by the activation of NF-kappaB participates in the intracellular signal transduction and production of cytokines and chemokines. The pathophysiological roles of p38 MAPK and NF-kappaB in human glomerulonephritis, however, remain to be investigated. Methods. We investigated the phosphorylated p38 MAPK (p-p38 MAPK) and activated NF-kappaB 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-1alpha, the cognate ligand for CCR5, were determined by enzyme-linked immunosorbent assay. Results. p-p38 MAPK-positive cells and activated NF-kappaB-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 hi-her 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-1alpha levels. In addition, the number of activated NF-kappaB-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-kappaB-positive cells decreased during glucocorticoid therapy-induced convalescence. Conclusions. We conclude that the phosphorylation of p38 MAPK associated with the activation of NF-kappaB may be involved in the upregulation of intrarenal MIP-1alpha and the utilization of CCR5 signalling, which may result in human crescentic glomerulonephritis.