Mouse mast cell protease-4 deteriorates renal function by contributing to inflammation and fibrosis in immune complex-mediated glomerulonephritis

Lisa Scandiuzzi, Walid Beghdadi, Eric Daugas, Magnus Åbrink, Neeraj Tiwari, Cristiana Brochetta, Julien Claver, Nassim Arouche, Xingxing Zang, Marina Pretolani, Renato C. Monteiro, Gunnar Pejler, Ulrich Blank

Research output: Contribution to journalArticle

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Abstract

Mast cells exert protective effects in experimental antiglomerular basement membrane-induced glomerulonephritis (GN), yet the responsible mediators have not been identified. In this study, we investigated the role of mouse mast cell protease (mMCP)-4, the functional homolog of human chymase, using mMCP-4-deficient mice. Compared with wild type animals, mMCP-4-deficient mice exhibited lower proteinuria, blood creatinine, and blood urea nitrogen levels, indicating an aggravating role of mMCP-4. Kidney histology confirmed less severe renal damage in mMCP-4-deficient mice with reduced deposits, glomerular and interstitial cellularity, and fibrosis scores. High amounts of mMCP-4 were detected in renal capsules, but not in the whole kidney, from wild type mice. Its expression in renal capsules was markedly decreased after GN induction, suggesting that locally released enzyme by degranulated mast cells could contribute to the functional and physiopathological hallmarks of GN. Supporting a proinflammatory role, glomerular and interstitial macrophage and T cell infiltration, levels of proinflammatory TNF and MCP-1 mRNA, and the expression of the profibrotic peptide angiotensin II together with type I collagen were markedly down-regulated in kidneys of mMCP-42deficient mice. We conclude that mMCP-4 chymase, contrary to the global anti-inflammatory action of mast cells, aggravates GN by promoting kidney inflammation. These results highlight the complexity of mast cell-mediated inflammatory actions and suggest that chymase inhibition may represent a novel therapeutic target in GN.

Original languageEnglish (US)
Pages (from-to)624-633
Number of pages10
JournalJournal of Immunology
Volume185
Issue number1
DOIs
StatePublished - Jul 1 2010

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Glomerulonephritis
Antigen-Antibody Complex
Fibrosis
Mast Cells
Inflammation
Kidney
Chymases
Capsules
Wild Animals
Blood Urea Nitrogen
Collagen Type I
mast cell protease 4
Proteinuria
Basement Membrane
Angiotensin II
Creatinine
Histology
Peptide Hydrolases
Anti-Inflammatory Agents
Macrophages

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Mouse mast cell protease-4 deteriorates renal function by contributing to inflammation and fibrosis in immune complex-mediated glomerulonephritis. / Scandiuzzi, Lisa; Beghdadi, Walid; Daugas, Eric; Åbrink, Magnus; Tiwari, Neeraj; Brochetta, Cristiana; Claver, Julien; Arouche, Nassim; Zang, Xingxing; Pretolani, Marina; Monteiro, Renato C.; Pejler, Gunnar; Blank, Ulrich.

In: Journal of Immunology, Vol. 185, No. 1, 01.07.2010, p. 624-633.

Research output: Contribution to journalArticle

Scandiuzzi, L, Beghdadi, W, Daugas, E, Åbrink, M, Tiwari, N, Brochetta, C, Claver, J, Arouche, N, Zang, X, Pretolani, M, Monteiro, RC, Pejler, G & Blank, U 2010, 'Mouse mast cell protease-4 deteriorates renal function by contributing to inflammation and fibrosis in immune complex-mediated glomerulonephritis', Journal of Immunology, vol. 185, no. 1, pp. 624-633. https://doi.org/10.4049/jimmunol.0902129
Scandiuzzi, Lisa ; Beghdadi, Walid ; Daugas, Eric ; Åbrink, Magnus ; Tiwari, Neeraj ; Brochetta, Cristiana ; Claver, Julien ; Arouche, Nassim ; Zang, Xingxing ; Pretolani, Marina ; Monteiro, Renato C. ; Pejler, Gunnar ; Blank, Ulrich. / Mouse mast cell protease-4 deteriorates renal function by contributing to inflammation and fibrosis in immune complex-mediated glomerulonephritis. In: Journal of Immunology. 2010 ; Vol. 185, No. 1. pp. 624-633.
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