Journal
KIDNEY INTERNATIONAL
Volume 84, Issue 2, Pages 317-326Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2013.98
Keywords
fibrosis; inflammation; mast cell chymase; unilateral ureteral obstruction
Categories
Funding
- French National Research Agency
- Investissements d'Avenir program [ANR-11-IDEX-0005-02]
- Sorbonne Paris Cite
- Laboratoire d'Excellence INFLAMEX
- 'Cardiovasculaire-Obesite-Diabete_Domaines d'Interet Majeurs' (CODDIM)
- European Community [BM1007]
- Agence Nationale de la Recherche (ANR) [ANR-11-IDEX-0005] Funding Source: Agence Nationale de la Recherche (ANR)
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Mast cell release of chymase is important in tissue remodeling and may participate in inflammation leading to fibrosis and organ failure. Here we analyzed the function of chymase in unilateral ureteral obstruction, an established accelerated model of renal tubulointerstitial fibrosis. Mice deficient in mouse mast cell protease 4 (mMCP4), the functional counterpart of human chymase, had increased obstruction-induced fibrosis when compared to wild-type mice indicating a protective effect of mMCP4. Engraftment of mast cell-deficient Kit(Wsh/Wsh) mice with wild type, but not mMCP4-deficient mast cells, restored protection confirming the role of mMCP4. Kidneys of mMCP4-deficient mice had higher levels of renal tubular damage, interstitial fibrosis, collagen deposition, increased alpha-smooth muscle actin, and decreased E-cadherin expression compared to the kidneys of wild-type mice. Further analysis showed an elevated inflammatory response in mMCP4-deficient mice with increased levels of kidney-infiltrating macrophages and T cells and local profibrotic TGF-beta 1 and CCL2. Granulated and degranulated mast cells and mMCP4 were mainly found in the kidney capsule, respectively, before and after ureteral obstruction. Analysis of mMCP4 substrates showed that it mediates its anti-fibrotic actions by degrading interstitial deposits of fibronectin, a known promoter of inflammatory cell infiltration and adhesion. Thus, mast cell released mMCP4 has anti-fibrotic potential in acutely induced obstructive nephropathy.
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