Delayed inhibition of p38 mitogen-activated protein kinase ameliorates renal fibrosis in obstructive nephropathy.
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.
Department 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
Masashi
M
Nishida
Yasuko
Y
Okumura
Hisashi
H
Sato
Kenji
K
Hamaoka
D000818:Animals; D001483:Base Sequence; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D017931:DNA Primers / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D005355:Fibrosis; D007674:Kidney Diseases / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D014517:Ureteral Obstruction / Q000150:complications*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D017931:DNA Primers; C104334:FR 167653; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases