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.
CONCLUSION: 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.

To the Editor

Summers et al[1] recently published their observations that mast cells are crucial to renal fibrosis induced by ureteral obstruction. This work confirmed our report showing that mast cells are required for the development of renal fibrosis in the rodent unilateral ureteral obstruction (UUO) model[2]. Our manuscript was published online September 28th, 2011. We would like to take this opportunity to expand on this role of mast cells in renal fibrosis, and advance a hypothesis for the underlying mechanism. In view of the fact that mast cells are found in close proximity to fibroblasts in UUO kidneys, we hypothesize that mast cell mediators released during degranulation are responsible for fibroblast proliferation and activation ultimately leading to fibrosis[3]. Recent findings from our lab demonstrate that kidney fibroblasts express the ANG II AT1 receptor (R) and the histamine H1R subtypes. Addition of ANG II and histamine to kidney fibroblasts in culture, promote proliferation, TGF-βsynthesis and collagen production[3]. These results, along with the findings of Veerappan et al[2] and Summers et al[1] suggest that release of mast cell mediators like renin (ANG II) and histamine, provide a mechanism that couples mast cell degranulation to fibroblast activation with the ensuing fibrosis. Targeting of mast cells and their products may represent novel therapeutic targets for preventing renal fibrosis.