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. K E Y W O R D Sfibrosis, inflammation, kidney, macrophage, neutrophil 2 of 13 | WANG et Al.

Prediction of severity and subtype of fibrosing disease using model informed by inflammation and extracellular matrix gene index

“…Matrix metalloproteinases (MMPs) are known to play a central role in fibrosis through their ability break down ECM constituents. Recent studies have also suggested a role for MMP upregulation in sustained inflammation through the immune cells chemoattraction and proliferation [ 54 , 55 ], particularly in older individuals [ 56 ], suggesting a role of MMP’s in the highly interdependent age and skin score correlations revealed through our Bayesian network projections ( Fig 2 ). Along with several other MMPs and their inhibitors, levels of MMP-1 show close association with SSc, and we found that gene expression differed between dSSc and lSSc patient profiles ( Fig 6 ).…”

Kidney research

“…To test whether or not the neutrophils play a role in the development of kidney fibrosis in this model the authors used neutrophil depletion by means of Ly6G antibody injection. Interestingly, interstitial collagen deposition was lower in the neutrophil‐depleted mice as compared to the isotype‐antibody treated obstructed mice 1 . The authors found by immunohistochemical staining that neutrophils are an important source for MMP9 in the obstructed kidney.…”

“…Kidney research has been one major focus of publications of recent articles published in Acta physiologica . A number of articles deal with the elucidation of kidney disease models 1‐12 and the role of oxygen regulation in the kidney 13‐16 . This contribution focusses on articles that deal with kidney disease models and in the second part on articles that are related to the topic hypoxia and oxygen regulation.…”

“…In the following section, we focus on three articles that make use of the unilateral ureter obstruction model. The unilateral ureter obstruction (UUO) is one animal model for the analysis of post‐renal failure that has been studied recently 1,3,12 . The models of the (UUO) have a clinical correlate, the hydronephrosis that can occur even prenatally 17 …”

“…In a work by Wang et al the role of the matrix metalloproteinase‐9 (MMP9) and neutrophils was analysed in this disease model 1 . The enzyme MMP9 is thought to be important in the process of neutrophil invasion in the kidney.…”