At a time when patients with lupus, or systemic lupus erythematosus (LED), are diagnosed, around 15% to 30% will already have the renal lupus nephritis caused by inflammation, which compromises kidney function and can cause renal failure. Between 30% and 50% of LED patients, will eventually develop lupus nephritis, and half of them will eventually develop a terminal kidney disease.
A research team from the South Carolina University of Medicine led by Jim Oates, MD, director of the rheumatology and immunology division and vice-president of research in the Department of Medicine, develops a new approach to prevent lupus nephritis-improving the health and function of the cells that line the kidney vessels, or renal endotheal cells.
The team reports in Lupus Science & Medicine that the exposure of renal endothelial cells to the serum of patients with lupus nephrite which experiences a thrust caused cell dysfunction, resulting in inflammation. On the other hand, when these same cells were exposed simultaneously to the widening of the lupus nephrite serum and the investigative drug L-Sepiapère, inflammation has been reduced and the genes associated with the production of nitric oxide, known to be protective against inflammation, have been improved. The serum was obtained from a biobank with specimens of patients with lupus, and the South Carolina Clinical and Translation Institute helped by the transformation and the samples bank.
In patients with LED, an autoimmune disease, the body brings together its immune defenses not against an invasive germ but against the body itself, causing inflammation, tissue lesions and sometimes an insufficiency of organ. In the nephritis lupus, it is the kidney which is targeted by the immune system.
“I compare this targeting by the immune system to what is happening after a transplant,” said Oates. “Thus, patients who have had a transplanted kidney require drugs that remove the immune system to avoid rejection. In the case of those with lupus nephritis, they reject their own kidney. »»
Immune removal has also been essential therapy for patients with lupus nephritis, but it leads to a cost – patients become much more vulnerable to infection.
The processing approach developed by the Oates laboratory does not remove the functions of the natural body, such as immunity, but uses pharmaceutical products to use inflammation and establish a more protective environment for endothelial cells, allowing proper functioning.
“When the endothelial cells border your blood vessels are altered, it endangers people for things like heart attacks and strokes, but also inflammatory or scars in the kidney. This puts people in damage to damage to organs, “said Oates. “This is a major objective of my laboratory – to restore the protective effects of correctly functional endothelial cells. »»
The director of the Oates laboratory, Dayvia Russell, the first author of the recent publication, sums up the new approach.
“The vascular system is the gateway to your organs,” she said. “The concept of our research is to try to protect the kidneys in patients with lupus nephritis by preventing vascular damage. »»
The key to maintaining healthy endothelial cells is the production of nitric oxide molecule, which can protect against inflammation and oxidative stress as well as to maintain a healthy blood flow and prevent leaks from immune cells in the tissue. However, oxidative stress, such as that produced by the risk factors of chronic disease, such as obesity, smoking and diabetes, can cause dysfunction of endothelial cells, which makes inflammation more likely.
More specifically, oxidative stress interrupts the production of nitric oxide by deactivating the nitric endothelial enzyme synthase (ENOS), causing the production of superoxide, a powerful free radical. The superoxide has an unpaid electron, making it very reactive and farnime of other molecules.
“Enos is a Yin and Yang molecule,” said Oates. “When it works properly, it can produce nitric oxide, which is protective against inflammation, but when it is not, it can have the opposite effect, which makes superoxide which causes oxidative stress. »»
In their study, musk researchers have shown the impact of the nephritis lupus for the first time on the genetic profile of renal endothelial cells and the ways in which the-screen-and-firing, which improves the function of Enos, modifies these genetic profiles. The team has shown that the exposure of renal endothelial cells to the serum of patients with lupus nephrite thrust has led to a higher expression of genes associated with inflammation. On the other hand, the simultaneous exposure of renal endothelial cells both in serum of lupus nephrite and L-SEPIPTERINE has led to a decrease in the expression of the genes associated with oxidative stress and an increased expression of the genes associated with the production of nitric oxide, suggesting a protective effect.
This research line is new in that it seeks to control the inflammatory environment which can cause damage to tissues and organs, not by removing the immune system, which can leave people sensitive to infection, but by using pharmaceuticals to adjust natural cellular processes to restore the function of endothelial cells and thus protect against inflammation.
If these results are confirmed in animal studies on mice subject to lupus, the team would then like to carry out a study of proof of small -scale concept in humans once it obtains the necessary funding.
The results could also have implications for the use of L-Spi-testrics in diseases other than lupus nephritis, said Russell. One of the genes increased with L-Sepiapère is known to be reduced in the kidney in type 2 diabetes.
“This suggests that L-Sepiapère has potential not only in the treatment of lupus nephritis but also other vascular diseases and perhaps even type 2 diabetes,” she said.