Role of mast cells in the development of renal fibrosis: use of mast cell-deficient rats.
BACKGROUND
Recent clinical studies have shown that the number of interstitial mast cells increases in various types of renal disease and correlates well with the magnitude of interstitial fibrosis. The present study was conducted to assess the role of mast cells in renal fibrosis by examining an experimental glomerular disease.


METHODS
A rat model of chronic glomerular disease, puromycin aminonucleoside-nephrosis, was induced in mast cell-deficient (Ws/Ws) and normal (+/+) rats.


RESULTS
The area of interstitial fibrosis was widely distributed at 6 weeks in both groups of rats; however, unexpectedly, the area of interstitial fibrosis was greater in Ws/Ws rats than in +/+ littermates. Biochemical analysis of the hydroxyproline content confirmed the more severe fibrosis in the Ws/Ws rats. The number of mast cells increased in both Ws/Ws and +/+ rats, concomitant with the development of interstitial fibrosis, but was confirmed to be lower in Ws/Ws than in +/+ rats. There were no differences in the numbers of interstitial macrophages and T lymphocytes between the two groups. Reverse transcription-polymerase chain reaction analysis of cytokine expression revealed that the level of mRNA for transforming growth factor-beta (TGF-beta), a potent profibrotic cytokine, was higher in Ws/Ws rats. In addition, heparin, one of the major components of mast cells, inhibited the expression of TGF-beta mRNA in rat fibroblasts in culture.


CONCLUSIONS
These results suggest that mast cells do not play a major role in the pathogenesis of interstitial fibrosis in puromycin aminonucleoside nephrosis. Rather, they might be protective or ameliorative in this model through the inhibition of TGF-beta production by heparin, and possibly in other models and also in humans.
Miyazawa
Shinobu
S
Department of Clinical Pharmacology, Research Institute, International Medical Center of Japan, Tokyo, Japan.
Hotta
Osamu
O
Doi
Naoko
N
Natori
Yumiko
Y
Nishikawa
Kiyotaka
K
Natori
Yasuhiro
Y
D000818:Animals; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D015847:Interleukin-4 / Q000235:genetics; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008407:Mast Cells / Q000473:pathology* / Q000502:physiology*; D011692:Puromycin Aminonucleoside / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D016212:Transforming Growth Factor beta / Q000235:genetics
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D011692:Puromycin Aminonucleoside; D006493:Heparin