TY - JOUR
T1 - Mast cell activation and degranulation promotes renal fibrosis in experimental unilateral ureteric obstruction
AU - Summers, Shaun Andrew
AU - Gan, Poh-Yi
AU - Dewage, Lakshi Teleshia
AU - Ma, Frank
AU - Ooi, Joshua
AU - O'Sullivan, Kim
AU - Nikolic-Paterson, David J
AU - Kitching, Arthur Richard
AU - Holdsworth, Stephen Roger
PY - 2012
Y1 - 2012
N2 - Progressive renal fibrosis is the final common pathway leading to renal failure irrespective of the initiating cause. Clinical studies of renal fibrosis found that prominent mast cell accumulation correlated with worse outcomes. Mast cells are pluripotent innate immune cells that synthesize and secrete profibrotic mediators. Here we use mast cell-deficient (Kit(W-sh/W-sh)) mice to define a functional pathogenic role for these cells in the development of renal fibrosis. Intrarenal collagen deposition was significantly decreased in mast cell-deficient compared to wild-type mice 7 and 14 days after unilateral ureteric obstruction. The intrarenal expression of mRNAs for transforming growth factor-beta, alpha-smooth muscle actin, chemokines, and renal macrophages and CD4(+) T cells were also decreased in mast cell-deficient mice. Reconstitution of the mast cell population in mast cell-deficient mice with wild-type bone marrow-derived mast cells restored the pattern and intensity of renal fibrosis to levels seen in wild-type mice following ureteric ligation. Interestingly, the mast cells were recruited, activated, and degranulated within 6 h of ureteric ligation. A mast cell stabilizer that impairs degranulation, disodium chromoglycate, significantly attenuated renal fibrosis following ureteric ligation in wild-type mice. Thus, mast cells promote renal fibrosis and their targeting may offer therapeutic potential in the treatment of renal fibrosis.Kidney International advance online publication, 6 June 2012; doi:10.1038/ki.2012.211.
AB - Progressive renal fibrosis is the final common pathway leading to renal failure irrespective of the initiating cause. Clinical studies of renal fibrosis found that prominent mast cell accumulation correlated with worse outcomes. Mast cells are pluripotent innate immune cells that synthesize and secrete profibrotic mediators. Here we use mast cell-deficient (Kit(W-sh/W-sh)) mice to define a functional pathogenic role for these cells in the development of renal fibrosis. Intrarenal collagen deposition was significantly decreased in mast cell-deficient compared to wild-type mice 7 and 14 days after unilateral ureteric obstruction. The intrarenal expression of mRNAs for transforming growth factor-beta, alpha-smooth muscle actin, chemokines, and renal macrophages and CD4(+) T cells were also decreased in mast cell-deficient mice. Reconstitution of the mast cell population in mast cell-deficient mice with wild-type bone marrow-derived mast cells restored the pattern and intensity of renal fibrosis to levels seen in wild-type mice following ureteric ligation. Interestingly, the mast cells were recruited, activated, and degranulated within 6 h of ureteric ligation. A mast cell stabilizer that impairs degranulation, disodium chromoglycate, significantly attenuated renal fibrosis following ureteric ligation in wild-type mice. Thus, mast cells promote renal fibrosis and their targeting may offer therapeutic potential in the treatment of renal fibrosis.Kidney International advance online publication, 6 June 2012; doi:10.1038/ki.2012.211.
UR - http://www.nature.com/ki/journal/v82/n6/full/ki2012211a.html
U2 - 10.1038/ki.2012.211
DO - 10.1038/ki.2012.211
M3 - Article
SN - 0085-2538
VL - 82
SP - 676
EP - 685
JO - Kidney International
JF - Kidney International
IS - 6
ER -