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Involvement of p38 mitogen-activated protein kinase followed by chemokine expression in crescentic glomerulonephritis
1Department of Internal Medicine and Division of Blood Purificationd, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. twada@medf.m.kanazawa-u.ac.jp
Abstract:
p38 Mitogen-activated protein kinase (MAPK) is involved in the production and signal transduction of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, and chemokines in vitro. However, the crucial role of p38 MAPK in the inflammatory processes of crescentic glomerulonephritis in vivo remains to be investigated. We showed a dramatic decrease in IL-1beta-induced phosphorylation of p38 MAPK, not extracellular signal-regulated kinases 1/2 or jun NH2-terminal kinase, in rat cultured mesangial cells by FR167653. We explored the effects of FR167653 as a specific inhibitor of p38 MAPK on renal injury and subsequent renal expression of chemokines in a progressive experimental crescentic glomerulonephritis model in Wistar-Kyoto rats. Rats developed crescentic glomerulonephritis leading to glomerulosclerosis and interstitial fibrosis by 56 days after the administration of nephrotoxic sera. The number of phosphorylated p38 MAPK-positive cells, detected mainly in crescents, correlated well with the percentage of crescents and number of ED-1-positive cells. Phosphorylated p38 MAPK-positive cells were downregulated in glomeruli in rats with the daily subcutaneous administration of FR167653 for 6 days. Concomitantly, renal expression of macrophage inflammatory protein-1alpha and monocyte chemoattractant protein-1/monocyte chemotactic and activating factor was markedly reduced by day 6. The severity of glomerulosclerosis and interstitial fibrosis significantly decreased by day 56, and renal function was preserved. These results suggest that p38 MAPK phosphorylation is pivotal for crescentic glomerulonephritis, followed by the subsequent expression of renal chemokines. This study provides evidence that regulation of p38 MAPK is a novel appealing therapeutic target for crescentic glomerulonephritis.
Insights
p38 Mitogen-activated protein kinase (MAPK) plays a key role in crescentic glomerulonephritis. Inhibiting p38 MAPK with FR167653 reduced kidney injury, inflammation, and preserved renal function in rats.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- p38 Mitogen-activated protein kinase (MAPK) is implicated in inflammatory cytokine production and signaling.
- Its specific role in crescentic glomerulonephritis (CGN) in vivo is not well understood.
- Interleukin-1beta (IL-1beta) and chemokines are key mediators in CGN pathogenesis.
Purpose of the Study:
- To investigate the role of p38 MAPK in experimental crescentic glomerulonephritis.
- To evaluate the therapeutic potential of FR167653, a specific p38 MAPK inhibitor, in this model.
Main Methods:
- A progressive experimental crescentic glomerulonephritis model was established in Wistar-Kyoto rats using nephrotoxic sera.
- Rats were treated with FR167653 or vehicle.
- Renal injury, glomerulosclerosis, interstitial fibrosis, renal function, and expression of phosphorylated p38 MAPK, ED-1, macrophage inflammatory protein-1alpha, and monocyte chemoattractant protein-1 were assessed.
Main Results:
- FR167653 significantly reduced IL-1beta-induced p38 MAPK phosphorylation in rat mesangial cells.
- In vivo, FR167653 treatment decreased phosphorylated p38 MAPK-positive cells in glomeruli, correlating with reduced crescent formation and macrophage infiltration.
- Renal expression of key chemokines was markedly reduced, leading to decreased glomerulosclerosis and interstitial fibrosis, and preserved renal function.
Conclusions:
- p38 MAPK phosphorylation is crucial for the development of crescentic glomerulonephritis and subsequent chemokine expression.
- Targeting p38 MAPK with FR167653 demonstrates therapeutic potential for treating crescentic glomerulonephritis.