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NDT Advance Access published online on May 30, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn309
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


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

Masashi Nishida, Yasuko Okumura, Hisashi Sato and Kenji Hamaoka

Department of Pediatric Cardiology and Nephrology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan

Correspondence and offprint requests to: Masashi Nishida, Department of Pediatric Cardiology and Nephrology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. Tel: +81-75-251-5832; Fax: +81-75-251-5833; E-mail: mnishida{at}koto.kpu-m.ac.jp



  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-β1 and {alpha}1(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 {alpha}1(I) collagen mRNA level were decreased, no significant change was observed in the number of interstitial macrophages and TGF-β1 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.

Keywords: macrophage; obstructive nephropathy; p38 mitogen-activated protein kinase; renal fibrosis; unilateral ureteral obstruction

Received for publication: 12. 3.08
Accepted in revised form: 7. 5.08


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