Delayed inhibition of p38 mitogen-activated protein kinase ameliorates renal fibrosis in obstructive nephropathy.

Abstract

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.

• Authors: Masashi Nishida, Yasuko Okumura, Hisashi Sato, Kenji Hamaoka
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 23 Issue 8 Pg. 2520-4 (Aug 2008) ISSN: 1460-2385 [Electronic] England
• PMID: 18515792 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type I
• Collagen Type I, alpha 1 Chain
• DNA Primers
• FR 167653
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridines
• RNA, Messenger
• Transforming Growth Factor beta1
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Base Sequence
• Collagen Type I (genetics)
• Collagen Type I, alpha 1 Chain
• DNA Primers (genetics)
• Fibroblasts (drug effects, pathology)
• Fibrosis
• Kidney Diseases (enzymology, etiology, pathology, prevention & control)
• Macrophages (drug effects, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Time Factors
• Transforming Growth Factor beta1 (genetics)
• Ureteral Obstruction (complications)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)