Mast cell activation and degranulation promotes renal fibrosis in experimental unilateral ureteric obstruction

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)676 - 685
Number of pages10
JournalKidney International
Volume82
Issue number6
DOIs
Publication statusPublished - 2012

Cite this

@article{e1b386ed8e534dc2914eee43577782bf,
title = "Mast cell activation and degranulation promotes renal fibrosis in experimental unilateral ureteric obstruction",
abstract = "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.",
author = "Summers, {Shaun Andrew} and Poh-Yi Gan and Dewage, {Lakshi Teleshia} and Frank Ma and Joshua Ooi and Kim O'Sullivan and Nikolic-Paterson, {David J} and Kitching, {Arthur Richard} and Holdsworth, {Stephen Roger}",
year = "2012",
doi = "10.1038/ki.2012.211",
language = "English",
volume = "82",
pages = "676 -- 685",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Elsevier",
number = "6",

}

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

VL - 82

SP - 676

EP - 685

JO - Kidney International

JF - Kidney International

SN - 0085-2538

IS - 6

ER -