New nanoparticle approach targets kidney damage in vasculitis
Early research shows protection in lab cells and animal models of ANCA-GN
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Small particles loaded with manganese, an essential trace mineral, may help protect the kidneys from damage related to ANCA-associated vasculitis (AAV) by restoring antioxidant defenses and blocking a form of immune-mediated cell death.
These findings come from experiments using neutrophils isolated from the blood of people with ANCA-associated glomerulonephritis (ANCA-GN), kidney endothelial cell models, and rat models of vasculitis-related glomerulonephritis.
Naturally present in water and many foods, including whole grains, nuts, and legumes, manganese is known to boost the activity of many enzymes (a type of protein) in metabolism, antioxidant defense, and other processes.
“These findings offer novel insights into the [disease-causing mechanisms] of AAV and present promising therapeutic strategies,” the researchers wrote in “Manganese-loaded carbon nanoparticles ameliorate ANCA-associated vasculitis by inhibiting ferroptosis,” which was published in the Journal of Nanobiotechnology.
How ANCA-related vasculitis damages blood vessels and kidneys
AAV occurs when an abnormal immune response, typically driven by self-reactive antibodies called ANCAs, causes inflammation and damage in small blood vessels throughout the body.
Although the disease can affect many organs, the kidneys are most often involved. Kidney involvement commonly appears as glomerulonephritis, which can impair the kidneys’ ability to remove waste and lead to serious complications.
While AAV’s underlying mechanisms are not completely understood, researchers believe that by targeting proteins in immune cells called neutrophils, ANCAs can overactivate these cells, leading them to damage neighboring endothelial cells, which line blood vessels.
Neutrophils can also release weblike structures to trap and kill microbes — called neutrophil extracellular traps, or NETs — which are thought to play a major role in AAV-related kidney damage. NETs have been shown to promote ferroptosis, a type of cell death linked to iron buildup and damage to fats in cell membranes ,lipid peroxidation.
While ferroptosis has been implicated in the development of some autoimmune diseases, “the exact role of ferroptosis in AAV-induced renal injury remains unknown,” the researchers wrote.
Researchers examine immune cells and kidney injury markers
To better understand the mechanisms behind AAV-GN, a team of researchers in China first analyzed neutrophils isolated from the blood of people with AAV-GN and healthy individuals.
They found that neutrophils from patients released significantly more NETs than those from healthy people. NETs were also significantly more abundant in the blood and the kidneys of people with AAV-GN, with higher NET levels linked to greater levels of markers of endothelial cell damage. Similar observations were made in rat models of AAV-GN.
The researchers then investigated whether ferroptosis was occurring in the kidneys by analyzing serum levels of several molecules involved in this form of cell death.
Compared with healthy people, those with AAV-GN had significantly higher serum levels of ferritin, a protein that stores iron, and malondialdehyde, a product of lipid peroxidation. They also had significantly lower manganese superoxide dismutase (MnSOD) activity, an antioxidant enzyme that protects cells against oxidative stress.
Oxidative stress, a form of cell damage caused by an imbalance between cell-damaging reactive oxygen species and antioxidant defenses, is known to contribute to ferroptosis.
Also, kidney tissues from people with AAV-GN and rat models showed significantly higher levels of TFR1, which helps bring iron into cells, and significantly lower levels of GPX4, an enzyme that normally protects cells from ferroptosis. Together, these changes suggest that ferroptosis is active in the kidneys during AAV-GN.
Nanoparticles tested as a way to protect kidney cells
The researchers then explored whether treatment with tiny particles loaded with manganese could be a potential strategy for AAV-GN by restoring antioxidant defenses.
The particles, called manganese-loaded glucose-based carbon nanoparticles (GCNPs/Mn), can enter cells and release manganese inside lysosomes — structures in cells that contain enzymes — where it may boost MnSOD activity. The goal was to restore antioxidant defenses and block ferroptosis.
In the lab, GCNPs/Mn were taken up by glomerular endothelial cell models and restored MnSOD activity. This reduced oxidative stress, prevented NET-induced ferroptosis, and improved the function of mitochondria, the cell’s powerhouses. GCNPs/Mn also reduced activation of signaling pathways involved in inflammation and endothelial cell damage.
In rat models of AAV-GN, treatment with GCNPs/Mn reduced kidney damage, with lower levels of oxidative stress and iron overload, as well as improved MnSOD activity. These changes were associated with less kidney inflammation compared with untreated rats.
While the study did not examine which stage AAV-GN might respond best to GCNPs/Mn, “further investigations are warranted to elucidate this aspect and optimize the clinical potential of GCNPs/Mn in AAV,” the researchers wrote.
