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Delayed inhibition of p38 mitogen-activated protein kinase ameliorates renal fibrosis in obstructive nephropathy
Masashi Nishida1, Yasuko Okumura, Hisashi Sato
1Department of Pediatric Cardiology and Nephrology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto 602-8566, Japan. mnishida@koto.kpu-m.ac.jp
Background:
The p38 mitogen-activated protein kinase (MAPK) pathway is an important intracellular signalling pathway involved in the production of proinflammatory and profibrotic mediators. Previous reports indicated the role of p38 MAPK activation in renal fibrosis.
Methods:
We administered a selective p38 alpha MAPK inhibitor, FR167653, in a mouse model of unilateral ureteral obstruction (UUO) during the late stage (Days 7-14) after UUO, and the kidneys were examined at Day 14. p38 and phospho-p38 MAPK protein levels, the degree of renal fibrosis, the degree of myofibroblast accumulation and macrophage infiltration, and mRNA levels for TGF-beta1 and alpha1(I) collagen in the kidneys were assessed.
Results:
FR167653 treatment caused marked decreases in phospho-p38 MAPK levels along with decreased fibrosis at Day 14 after UUO. Although myofibroblast accumulation and alpha1(I) collagen mRNA level were decreased, no significant change was observed in the number of interstitial macrophages and TGF-beta1 mRNA level with FR167653 treatment.
Conclusions:
These results suggest that p38 MAPK blockade is an appealing therapeutic target, even after the emergence of established fibrosis.
Insights
Blocking the p38 mitogen-activated protein kinase (MAPK) pathway with FR167653 reduced established renal fibrosis in a mouse model. This suggests p38 MAPK is a viable therapeutic target for kidney fibrosis.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- The p38 mitogen-activated protein kinase (MAPK) pathway regulates inflammatory and fibrotic mediators.
- p38 MAPK activation is implicated in the development of renal fibrosis.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting the p38 MAPK pathway in established renal fibrosis.
- To evaluate the effects of a selective p38 alpha MAPK inhibitor, FR167653, in a late-stage mouse model of kidney fibrosis.
Main Methods:
- A selective p38 alpha MAPK inhibitor, FR167653, was administered to mice with established unilateral ureteral obstruction (UUO)-induced renal fibrosis.
- Kidneys were analyzed for p38 MAPK activation, fibrosis, myofibroblast accumulation, macrophage infiltration, and specific gene expression.
Main Results:
- FR167653 treatment significantly reduced phospho-p38 MAPK levels and overall renal fibrosis.
- Myofibroblast accumulation and alpha1(I) collagen mRNA levels were decreased by FR167653.
- No significant changes were observed in macrophage infiltration or TGF-beta1 mRNA levels.
Conclusions:
- p38 MAPK blockade effectively reduces established renal fibrosis, even in later stages.
- Targeting the p38 MAPK pathway represents a promising therapeutic strategy for kidney fibrosis.
