At the time when patients with lupus, or systemic lupus erythematosus (SLE), are diagnosed, approximately 15% to 30% will already have the inflammation-caused kidney disease lupus nephritis, which compromises kidney function and can lead to kidney failure. Between 30% and 50% of SLE patients will ultimately go on to develop lupus nephritis, and half of them will eventually develop end-stage renal disease.
A Medical University of South Carolina research team led by Jim Oates, M.D., director of the Division of Rheumatology and Immunology and vice chair for Research in the Department of Medicine, is developing a new approach to preventing lupus nephritis – improving the health and function of the cells that line the kidney blood vessels, or renal endothelial cells, to prevent immune cells from leaking into kidney tissue and damaging it.
The team reports in Lupus Science & Medicine that the exposure of renal endothelial cells to serum from patients with lupus nephritis who are experiencing a flare caused the cells to malfunction, leading to inflammation. In contrast, when those same cells were exposed simultaneously to flare lupus nephritis serum and the investigational drug L-sepiapterin, inflammation was reduced, and genes associated with the production of nitric oxide, known to be protective against inflammation, were enhanced. Serum was obtained from a biobank with specimens from patients with lupus, and the South Carolina Clinical & Translational Research Institute assisted with the processing and banking of samples.
In patients with SLE, an autoimmune disease, the body musters its immune defenses not against an invading germ but against the body itself, causing inflammation, tissue damage and sometimes organ failure. In lupus nephritis, it is the kidney that is targeted by the immune system.
“I liken this targeting by the immune system to what happens after a transplant,” said Oates. “So patients who have had a transplanted kidney require drugs that suppress the immune system to prevent rejection. In the case of those with lupus nephritis, they’re rejecting their own kidney.”
Immune suppression has also been the go-to therapy for patients with lupus nephritis, but it carries a cost – patients become much more vulnerable to infection.
The treatment approach being developed by the Oates Lab does not suppress natural body functions, such as immunity, but uses pharmaceuticals to dial back inflammation and establish a more protective environment for endothelial cells, enabling proper functioning.
“When the endothelial cells that line your blood vessels are impaired, it puts people at risk for things like heart attacks and strokes but also inflammatory or scarring events in the kidney. It puts people at risk for organ damage,” said Oates. “That’s a major focus of my laboratory – to restore the protective effects of properly functioning endothelial cells.”
Oates Laboratory manager Dayvia Russell, first author of the recent publication, sums up the new approach.
“The vasculature 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 maintenance of healthy endothelial cells is the production of the molecule nitric oxide, which can protect against inflammation and oxidative stress as well as help to maintain healthy blood flow and prevent leakage of immune cells into the tissue. However, oxidative stress, such as that produced by risk factors for chronic disease, such as obesity, smoking and diabetes, can cause endothelial cells to malfunction, making inflammation more likely.
Specifically, oxidative stress interrupts nitric oxide production by disabling the enzyme endothelial nitric oxide synthase (eNOS), causing superoxide, a powerful free radical, to be produced instead. Superoxide has an unpaired electron, making it highly reactive with and damaging to other molecules.
“eNOS is a yin and yang molecule,” said Oates. “When it’s functioning properly, it can produce nitric oxide, which is protective against inflammation, but when it’s not, it can have the opposite effect, making superoxide that causes oxidative stress.”
In their study, the MUSC researchers showed for the first time the impact of lupus nephritis on the genetic profile of renal endothelial cells and the ways in which L-sepiapterin, which enhances eNOS function, alters those genetic profiles. The team showed that the exposure of renal endothelial cells to serum from patients with a flare-up of lupus nephritis led to higher expression of genes associated with inflammation. In contrast, simultaneous exposure of renal endothelial cells to both flare lupus nephritis serum and L-sepiapterin resulted in decreased expression of genes associated with oxidative stress and increased expression of genes associated with nitric oxide production, suggesting a protective effect.
This line of research is novel in that it seeks to control the inflammatory environment that can cause tissue and organ damage, not by suppressing the immune system, which can leave people susceptible to infection, but by using pharmaceuticals to adjust the natural cell processes to restore endothelial cell function and thereby protect against inflammation.
If these findings are borne out in animal studies of lupus-prone mice, the team would next like to perform a small-scale proof-of-concept study in humans once it obtains the necessary funding.
The findings could also have implications for L-sepiapterin use in diseases other than lupus nephritis, said Russell. One of the genes increased with L-sepiapterin is known to be reduced in the kidney in Type 2 diabetes.
“This suggests that L-sepiapterin has potential not only in the treatment of lupus nephritis but also other vascular diseases and maybe even Type 2 diabetes,” she said.
Source:
Medical University of South Carolina