MMP-9-positive neutrophils are essential for establishing profibrotic microenvironment in the obstructed kidney of UUO mice.

Abstract

AIM:

Matrix metalloproteinase-9 (MMP9) plays a profibrotic role in renal fibrosis. Neutrophils produce MMP9 in many pathologic models. However, the effect of neutrophil on the progression of renal fibrosis and the relationship of MMP9 to the infiltration of neutrophils into the kidney remain unknown.

METHODS:

The surgery of unilateral ureter obstruction (UUO) was performed in male C57BL/6 mice. Kidneys were collected for analyses on days 0, 1, 3, 5 or 7 following surgery. The inflammatory cells were analysed by flow cytometry. The mRNA and protein levels of renal fibrosis factor and inflammatory factor were measured by qRT-PCR, immumofluorescence and western blot analysis.

RESULTS:

In a mouse kidney model of UUO, neutrophil infiltration significantly increased and neutrophil accumulation reached the highest level at 5 days after the injury. In the obstructed kidney, depleting neutrophils decreased the expression of inflammatory factors, inhibited the accumulation of macrophages including type 2 macrophages and suppressed renal fibrosis. Almost all neutrophils produced MMP9 at the early stage of kidney obstruction. MMP9 attracted neutrophils and inflammatory cells because inhibiting MMP9 suppressed the infiltration of neutrophils and other inflammatory cells and reduced renal fibrosis, regardless of using MMP9 neutralizing antibody or MMP9 inhibitor or different intervening periods of days (0-6, 0-3 or 3-6 were applied after kidney obstruction).

CONCLUSION:

MMP9 promotes neutrophil infiltration by increasing the inflammatory level, macrophage accumulation and renal fibrosis in the obstructed kidney. Inhibiting MMP9 or depleting neutrophils in the early stage of acute kidney injury can relieve the progression of kidney fibrosis.

• Authors: Haidong Wang, Min Gao, Jiangbo Li, Jian Sun, Ran Wu, Deping Han, Jianmei Tan, Juan Wang, Bin Wang, Liping Zhang, Yanjun Dong
• Journal: Acta physiologica (Oxford, England) (Acta Physiol (Oxf)) Vol. 227 Issue 2 Pg. e13317 (10 2019) ISSN: 1748-1716 [Electronic] England
• PMID: 31132220 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Chemical References

• Matrix Metalloproteinase 9

Topics

• Animals
• Cellular Microenvironment
• Fibrosis
• Kidney Diseases (pathology, physiopathology)
• Macrophages
• Male
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neutrophils (physiology)
• Ureteral Obstruction (metabolism)