The role of p38alpha mitogen-activated protein kinase activation in renal fibrosis.
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 p38alpha, 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-beta1 mRNA and protein levels in UUO was unaltered with NPC 31169 treatment; however, connective tissue growth factor mRNA was reduced. These results demonstrate that p38alpha MAPK plays an important role in renal fibrosis, acting downstream of TGF-beta1. Blockade of p38 MAPK reduces extracellular matrix production and may be considered a potential therapeutic option in the treatment of renal fibrosis.
Stambe
Cosimo
C
Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia. cosimo.stambe@med.monash.edu.au
Atkins
Robert C
RC
Tesch
Greg H
GH
Masaki
Takao
T
Schreiner
George F
GF
Nikolic-Paterson
David J
DJ
D000818:Animals; D004789:Enzyme Activation; D005260:Female; D005355:Fibrosis; D007668:Kidney / Q000201:enzymology* / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000150:complications; D048051:p38 Mitogen-Activated Protein Kinases
D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases