At the time of diagnosis, approximately 15% to 30% of patients with systemic lupus erythematosus (SLE) already suffer from lupus nephritis, a kidney disease caused by inflammation that compromises kidney function and can lead to kidney failure. Ultimately, between 30% and 50% of SLE patients will develop lupus nephritis, with half of these cases progressing to end-stage renal disease.
A research team at the Medical University of South Carolina (MUSC), led by Dr. Jim Oates, is pioneering a new approach to prevent lupus nephritis by enhancing the health and function of renal endothelial cells. These cells line the kidney blood vessels and play a crucial role in preventing immune cells from leaking into kidney tissue and causing damage.
Breakthrough in Lupus Nephritis Research
In a recent study published in Lupus Science & Medicine, the MUSC team reported that renal endothelial cells exposed to serum from lupus nephritis patients experiencing a flare showed signs of malfunction and inflammation. However, when these cells were simultaneously exposed to the investigational drug L-sepiapterin, inflammation was reduced, and genes associated with nitric oxide production, which protects against inflammation, were enhanced.
Dr. Jim Oates emphasized the importance of endothelial cell function, stating, “When the endothelial cells that line your blood vessels are impaired, it puts people at risk for organ damage. That’s a major focus of my laboratory – to restore the protective effects of properly functioning endothelial cells.”
The Challenge of Autoimmune Diseases
Lupus nephritis is a complication of SLE, an autoimmune disease where the body’s immune system attacks its own tissues, causing inflammation and organ damage. Dr. Oates likened this immune targeting to organ transplant rejection, where patients require immunosuppressive drugs to prevent rejection.
While immune suppression has been the traditional therapy for lupus nephritis, it increases the risk of infection. The approach being developed by the Oates Lab aims to reduce inflammation and create a protective environment for endothelial cells without suppressing natural immune functions.
Innovative Treatment Strategies
Dayvia Russell, Oates Laboratory manager and first author of the study, explained the research’s focus on protecting kidneys by preventing vascular damage. “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.”
Healthy endothelial cells produce nitric oxide, a molecule that protects against inflammation and oxidative stress while maintaining healthy blood flow. However, oxidative stress from factors like obesity, smoking, and diabetes can disrupt nitric oxide production, leading to inflammation.
“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.”
Future Implications and Broader Applications
The MUSC researchers demonstrated for the first time the impact of lupus nephritis on the genetic profile of renal endothelial cells and how L-sepiapterin alters these profiles. Their findings suggest a protective effect, with decreased expression of genes associated with oxidative stress and increased expression of genes linked to nitric oxide production.
This novel research seeks to control the inflammatory environment that causes tissue and organ damage by adjusting natural cell processes rather than suppressing the immune system. If successful in animal studies, the team hopes to conduct a small-scale proof-of-concept study in humans.
Dayvia Russell noted that the findings could extend beyond lupus nephritis, potentially benefiting other vascular diseases and even 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.
The research by Dr. Oates and his team represents a significant step forward in understanding and potentially treating lupus nephritis. As they continue to explore the possibilities of L-sepiapterin, the implications for patients with SLE and other related conditions could be profound, offering hope for improved management and outcomes.
