Researchers Develop New Mouse Model of Kidney Injury in AAV
A team of scientists in Europe has developed a novel mouse model of the type of kidney damage that commonly occurs in ANCA-associated vasculitis (AAV), and identified the receptor CXCR4 as a potential target for future therapies.
“This model may be a considerable benefit to research aimed at ameliorating progression of renal [kidney] injury in AAV,” the team wrote.
The researchers described their model in a study, “An adapted passive model of anti-MPO dependent crescentic glomerulonephritis reveals matrix dysregulation and is amenable to modulation by CXCR4 inhibition,” published in Matrix Biology.
AAV is an autoimmune disorder characterized by inflammation in small blood vessels. This inflammation is driven in part by self-reactive antibodies, and it can cause damage to many organs and tissues.
The kidneys, which contain small blood vessels that help filter waste from the body, are especially vulnerable to damage from AAV. Focal necrotizing glomerulonephritis, or FNGN, is a particular kind of kidney damage characterized by inflammation and scarring of kidney tissue that is often seen in AAV.
To understand the biological processes that drive FNGN, it is necessary to have laboratory models that can accurately recapitulate aspects of the disease. Mouse models are commonly used to mimic human diseases, but existing models of FNGN are limited. Specifically, current models generally don’t exhibit the type of progressive kidney scarring that usually is seen in humans with AAV.
The researchers set out to create a mouse model that better reflects these processes. In the model, mice first were treated with low amounts of an antibody targeting the glomerular basement membrane (GBM), an important component of kidney tissue. The point of this treatment was to “prime” the kidneys for AAV-like damage.
Five days after the anti-GBM treatment, mice were treated with antibodies against myeloperoxidase (MPO) — one of the most common AAV-associated antibodies in humans with the disease. Although other models have used antibodies taken from patients, here the researchers used two lab-made anti-MPO antibodies to ensure consistency across experiments.
At the same time, mice were treated with anti-MPO antibodies, they also were treated with lipopolysaccharide (LPS), a bacterial molecule that potently activates the immune system.
The team conducted a series of detailed analyses on the mice’s kidneys; broadly, results indicated that damage in this model was similar to what is seen in human disease. The researchers also showed that the model could be used to follow chronic kidney damage that occurs over time.
“These results show that our adapted protocol employing anti-GBM, two monoclonal anti-MPO antibodies and LPS together is sufficient to induce severe FNGN with crescent formation [a sign of kidney damage] in mice, resembling human AAV,” the researchers concluded.
“This model recapitulates several important [clinical and disease-related] features of chronic injury observed after FNGN in AAV patients,” they added.
Further investigation of the model showed that the FNGN-inducing treatment led to a substantial increase in the number of immune cells in the mice’s kidneys. Many of these immune cells expressed high levels of CXCR4, which is a protein receptor that plays a central role in governing immune cell activity.
Treating the mice with an inhibitor of CXCR4 did not decrease the number of immune cells in the kidneys, nor did it alter most markers of kidney damage. However, analyses of the proteins in the kidneys indicated that there were overall lower levels of certain inflammatory proteins in mice treated with the CXCR4 inhibitor, suggesting reduced immune cell activation.
“These results suggest that immune cell activation and injury in our anti-MPO antibody model of AAV are sensitive to inhibition of CXCR4,” the researchers wrote, noting that this protein receptor might be an interesting target to explore in future studies.
More broadly, the result “exemplifies that our model is suitable for pre-clinical studies of pharmacological intervention at early and late stages of renal injury AAV,” the team concluded.