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The Role of p38 Mitogen-Activated Protein Kinase Activation in Renal Fibrosis

Cosimo Stambe^*,, Robert C. Atkins^*,, Greg H. Tesch^*,, Takao Masaki^*, George F. Schreiner and David J. Nikolic-Paterson^*,

*Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia; and Scios Inc., San Francisco, California.

Correspondence to: Dr. Cosimo Stambe, Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Melbourne, Australia, 3168. Phone: 61-3-95943568; Fax: 61-3-9594-3650; E-mail: cosimo.stambe{at}med.monash.edu.au

ABSTRACT. The p38 mitogen-activated protein kinase (MAPK) pathway transduces external stress stimuli and is important in extracellular matrix synthesis in cell types in vitro; however, its role in renal fibrosis is not known. Explored was the role the p38 MAPK pathway in rat unilateral ureteric obstruction (UUO), a model of renal fibrosis induced by a noninflammatory surgical insult. In a time-course study, a marked increase in phosphorylation (activation) of p38 in both interstitial myofibroblasts and tubules was shown. Rats were then treated daily with a specific inhibitor of p38, NPC 31169, from the time of UUO surgery until being killed 7 d later. Compared with vehicle, NPC 31169–treated rats had a significant reduction in renal fibrosis assessed by interstitial volume, collagen IV deposition, and mRNA levels. This was primarily due to a reduction in the accumulation of interstitial myofibroblasts, as shown by a reduction in the area of immunostaining for alpha–smooth muscle actin and heat shock protein 47. The increase in renal TGF-1 mRNA and protein levels in UUO was unaltered with NPC 31169 treatment; however, connective tissue growth factor mRNA was reduced. These results demonstrate that p38 MAPK plays an important role in renal fibrosis, acting downstream of TGF-1. Blockade of p38 MAPK reduces extracellular matrix production and may be considered a potential therapeutic option in the treatment of renal fibrosis.

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