| 1. |
- Madjene, Lydia Celia, et al.
(author)
-
Mast cell chymase protects against acute ischemic kidney injury by limiting neutrophil hyperactivation and recruitment
- 2020
-
In: Kidney International. - : ELSEVIER SCIENCE INC. - 0085-2538 .- 1523-1755. ; 97:3, s. 516-527
-
Journal article (peer-reviewed)abstract
- Here we investigated the role of murine mast cell protease 4 (MCPT4), the functional counterpart of human mast cell chymase, in an experimental model of renal ischemia reperfusion injury, a major cause of acute kidney injury. MCPT4-deficient mice had worsened kidney function compared to wildtype mice. MCPT4 absence exacerbated pathologic neutrophil infiltration in the kidney and increased kidney myeloperoxidase expression, cell death and necrosis. In kidneys with ischemia reperfusion injury, when compared to wildtype mice, MCPT4-deficient mice showed increased surface expression of adhesion molecules necessary for leukocyte extravasation including neutrophil CD162 and endothelial cell CD54. In vitro, human chymase mediated the cleavage of neutrophil expressed CD162 and also CD54, P- and E-Selectin expressed on human glomerular endothelial cells. MCPT4 also dampened systemic neutrophil activation after renal ischemia reperfusion injury as neutrophils expressed more CD11b integrin and produced more reactive oxygen species in MCPT4-deficient mice. Accordingly, after renal injury, neutrophil migration to an inflammatory site distal from the kidney was increased in MCPT4-deficient versus wildtype mice. Thus, contrary to the described overall aggravating role of mast cells, one granule-released mediator, the MCPT4 chymase, exhibits a potent anti-inflammatory function in renal ischemia reperfusion injury by controlling neutrophil extravasation and activation thereby limiting associated damage.
|
|
| 2. |
- Pons, Maguelonne, et al.
(author)
-
Mast cells and McPT4 chymase Promote renal impairment after Partial Ureteral Obstruction
- 2017
-
In: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 8
-
Journal article (peer-reviewed)abstract
- Obstructive nephropathy constitutes a major cause of pediatric renal progressive disease. The mechanisms leading to disease progression are still poorly understood. Kidney fibrotic lesions are reproduced using a model of partial unilateral ureteral obstruction (pUUO) in newborn mice. Based on data showing significant mast cell (MC) infiltration in patients, we investigated the role of MC and murine MCPT4, a MC-released chymase, in pUUO using MC- (W-sh/sh), MCPT4-deficient (Mcpt4(-/-)), and wild-type (WT) mice. Measurement of kidney length and volume by magnetic resonance imaging (MRI) as well as postmortem kidney weight revealed hypotrophy of operated right kidneys (RKs) and compensatory hypertrophy of left kidneys. Differences between kidneys were major for WT, minimal for Wsh/sh, and intermediate for Mcpt4(-/-) mice. Fibrosis development was focal and increased only in WT-obstructed kidneys. No differences were noticed for local inflammatory responses, but serum CCL2 was significantly higher in WT versus Mcpt4(-/-) and Wsh/sh mice. Alpha-smooth muscle actin (alpha SMA) expression, a marker of epithelial-mesenchymal transition (EMT), was high in WT, minimal for W-sh/sh, and intermediate for Mcpt4(-/-) RK. Supernatants of activated MC induced aSMA in co-culture experiments with proximal tubular epithelial cells. Our results support a role of MC in EMT and parenchyma lesions after pUUO involving, at least partly, MCPT4 chymase. They confirm the importance of morphologic impairment evaluation by MRI in pUUO.
|
|
| 3. |
- Scandiuzzi, Lisa, et al.
(author)
-
Mouse mast cell protease-4 deteriorates renal function by contributing to inflammation and fibrosis in immune complex-mediated glomerulonephritis
- 2010
-
In: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 185:1, s. 624-633
-
Journal article (peer-reviewed)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 downregulated in kidneys of mMCP-4-deficient 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.
|
|
