Article

Activation of p38 mitogen-activated protein kinase promotes peritoneal fibrosis by regulating fibrocytes.

Department of Disease Control and Homeostasis, Institute of Medical, Pharmaceutical and Health Sciences, Faculty of Medicine, Kanazawa University, Kanazawa, Japan.
Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis 06/2011; 32(1):10-9. DOI:10.3747/pdi.2010.00200 pp.10-9
Source: PubMed

ABSTRACT Peritoneal fibrosis is a serious complication of long-term peritoneal dialysis, and yet the precise pathogenic mechanisms of peritoneal fibrosis remain unknown. Fibrocytes participate in tissue fibrosis and express chemokine receptors that are necessary for migration. The p38 mitogen-activated protein kinase (MAPK) pathway regulates the production of chemokines and has been demonstrated to contribute to the pathogenesis of various fibrotic conditions. Accordingly, we used an experimental mouse model of peritoneal fibrosis to examine the dependency of fibrocytes on p38MAPK signaling.
Peritoneal fibrosis was induced in mice by the injection of 0.1% chlorhexidine gluconate (CG) into the abdominal cavity. Mice were treated with FR167653, a specific inhibitor of p38MAPK, and immunohistochemical studies were performed to detect fibrocytes and cells positive for phosphorylated p38MAPK. The involvement of p38MAPK in the activation of fibrocytes also was also investigated in vitro.
Fibrocytes infiltrated peritoneum in response to CG, and that response was accompanied by progressive peritoneal fibrosis. The phosphorylation of p38MAPK, as defined by CD45+ spindle-shaped cells, was detected both in peritoneal mesothelial cells and in fibrocytes. The level of peritoneal expression of CCL2, a chemoattractant for fibrocytes, was upregulated by CG injection, and treatment with FR167653 reduced the number of cells positive for phosphorylated p38MAPK, the peritoneal expression of CCL2, and the extent of peritoneal fibrosis. Pretreatment with FR167653 inhibited the expression of procollagen type I α1 induced by transforming growth factor-β1.
Our results suggest that p38MAPK signaling contributes to peritoneal fibrosis by regulating fibrocyte function.

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  • Article: The role of p38alpha mitogen-activated protein kinase activation in renal fibrosis.
    Cosimo Stambe, Robert C Atkins, Greg H Tesch, Takao Masaki, George F Schreiner, David J Nikolic-Paterson
    [show abstract] [hide abstract]
    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 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.
    Journal of the American Society of Nephrology 03/2004; 15(2):370-9. · 9.66 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

0.1% chlorhexidine gluconate
 
abdominal cavity
 
CD45+ spindle-shaped cells
 
cells positive
 
chemokine receptors
 
experimental mouse model
 
Fibrocytes infiltrated peritoneum
 
growth factor-β1
 
immunohistochemical studies
 
long-term peritoneal dialysis
 
p38MAPK signaling contributes
 
Peritoneal fibrosis
 
peritoneal mesothelial cells
 
phosphorylated p38MAPK
 
precise pathogenic mechanisms
 
progressive peritoneal fibrosis
 
regulating fibrocyte function
 
serious complication
 
tissue fibrosis
 
various fibrotic conditions