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Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration
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Mast cell chymase protects against acute ischemic kidney injury by limiting neutrophil hyperactivation and

Lydia Celia Madjene1, Luca Danelli1, Albert Dahdah1

  • 1Center of Research on Inflammation, Inserm UMRS-1149, Paris, France; Center of Research on Inflammation, CNRS ERL 8252, Paris, France; Center of Research on Inflammation, Université Paris Diderot, Sorbonne Paris Cite, Laboratoire d'excellence INFLAMEX, Paris, France.

Kidney International
|December 24, 2019
PubMed

Insights

Murine mast cell protease 4 (MCPT4) protects kidneys during ischemia reperfusion injury. Lack of MCPT4 worsens kidney function by increasing neutrophil infiltration and activation, highlighting its anti-inflammatory role.

Area of Science:

  • Immunology
  • Nephrology
  • Molecular Biology

Background:

  • Renal ischemia reperfusion injury (IRI) is a significant cause of acute kidney injury.
  • Mast cell proteases, like murine mast cell protease 4 (MCPT4), play complex roles in inflammation.
  • MCPT4 is the functional counterpart of human mast cell chymase.

Purpose of the Study:

  • To investigate the role of MCPT4 in a murine model of renal IRI.
  • To determine if MCPT4 has a protective or detrimental effect on kidney function during IRI.
  • To elucidate the mechanisms by which MCPT4 influences neutrophil behavior in renal IRI.

Main Methods:

  • Utilized MCPT4-deficient mice and wildtype littermates subjected to renal IRI.
  • Assessed kidney function, histological damage, and neutrophil infiltration.
  • Analyzed expression of adhesion molecules (CD162, CD54, Selectins) on neutrophils and endothelial cells.
  • Evaluated neutrophil activation markers (CD11b, reactive oxygen species) and systemic neutrophil migration.
  • Performed in vitro cleavage assays using human chymase.

Main Results:

  • MCPT4-deficient mice exhibited worsened kidney function and increased renal pathology (necrosis, cell death) post-IRI.
  • Absence of MCPT4 led to exacerbated neutrophil infiltration and increased myeloperoxidase expression in kidneys.
  • MCPT4 deficiency resulted in elevated expression of leukocyte adhesion molecules (CD162, CD54) and increased neutrophil activation (CD11b, ROS).
  • Human chymase cleaved neutrophil CD162 and endothelial cell adhesion molecules (CD54, P- and E-Selectin) in vitro.
  • MCPT4-deficient mice showed increased neutrophil migration to distal inflammatory sites.

Conclusions:

  • MCPT4 exerts a potent anti-inflammatory effect in renal IRI.
  • MCPT4 limits kidney damage by controlling neutrophil extravasation and activation.
  • This study identifies MCPT4 as a protective mediator in renal IRI, contrasting with the generally aggravating role of mast cells.
Keywords:
acute kidney injuryacute rejectioninflammationischemia reperfusion

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