Masashi Nishida1, Yasuko Okumura, Hisashi Sato, Kenji Hamaoka. 1. 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
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.
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: John T Liles; Britton K Corkey; Gregory T Notte; Grant R Budas; Eric B Lansdon; Ford Hinojosa-Kirschenbaum; Shawn S Badal; Michael Lee; Brian E Schultz; Sarah Wise; Swetha Pendem; Michael Graupe; Laurie Castonguay; Keith A Koch; Melanie H Wong; Giuseppe A Papalia; Dorothy M French; Theodore Sullivan; Erik G Huntzicker; Frank Y Ma; David J Nikolic-Paterson; Tareq Altuhaifi; Haichun Yang; Agnes B Fogo; David G Breckenridge Journal: J Clin Invest Date: 2018-07-19 Impact factor: 14.808
Authors: Amélie Dendooven; David A Ishola; Tri Q Nguyen; Dionne M Van der Giezen; Robbert Jan Kok; Roel Goldschmeding; Jaap A Joles Journal: Int J Exp Pathol Date: 2010-08-27 Impact factor: 1.925
Authors: Diping Wang; Gina M Warner; Ping Yin; Bruce E Knudsen; Jingfei Cheng; Kim A Butters; Karen R Lien; Catherine E Gray; Vesna D Garovic; Lilach O Lerman; Stephen C Textor; Karl A Nath; Robert D Simari; Joseph P Grande Journal: Am J Physiol Renal Physiol Date: 2013-01-30
Authors: Mercedes N Munkonda; Shareef Akbari; Chloe Landry; Suzy Sun; Fengxia Xiao; Maddison Turner; Chet E Holterman; Rania Nasrallah; Richard L Hébert; Christopher R J Kennedy; Dylan Burger Journal: J Extracell Vesicles Date: 2018-02-02
Authors: Eugene Makarev; Evgeny Izumchenko; Fumiaki Aihara; Piotr T Wysocki; Qingsong Zhu; Anton Buzdin; David Sidransky; Alex Zhavoronkov; Anthony Atala Journal: Cell Cycle Date: 2016-06-07 Impact factor: 4.534