Metabolic Reprogramming in Lupus Nephritis
Abstract
Systemic lupus erythematosus (lupus) affects 1 to 2 million Americans and millions more worldwide. Fifty percent of lupus patients will develop lupus nephritis, a severe kidney disease associated with lupus that is responsible for significant disability and death. Current treatments have significant side effects, high failure rates, and patients often have recurrence of the disease. While our understanding of lupus nephritis has grown over the last several decades, no new or targeted therapies have been developed in recent years. Thus, it is necessary that the research community continues to investigate causes of lupus nephritis and develop new treatment modalities. Immune system abnormalities are a central mediator of lupus organ damage. Thus, much of the research in lupus nephritis has focused on inhibiting or eliminating the specific immune cells that are thought to be responsible for disease. The cells of the kidney and their relationship in the development of lupus nephritis is not well described. We know from other kidney disease that kidney cells undergo changes after suffering damage from toxic chemicals, low blood flow, or inflammation from invading immune cells. The metabolic function of the kidney, specifically how well the kidney uses oxygen, sugars, and fats to repair itself, create energy, and make new building blocks for proteins, is an area of focus in other kidney disease. We hypothesize that the metabolic function of kidney cells will be altered by the damage the cells sustain from inflammation in lupus nephritis. We also hypothesize that the kidney cells may act in some way to suppress the invading immune cells in lupus nephritis as a way of protecting the kidney from ongoing damage. In this study, we plan to study kidney cells directly to see how they are metabolically changed in lupus nephritis. Secondarily, we will see if the metabolic changes that occur in these kidney cells due to lupus nephritis alter how the invading immune cells function. This work will directly address the Lupus Research Programs focus area of determining the pathobiology of lupus disease in target human tissue. If we are able to identify metabolic changes that are occurring in the lupus kidney, and if these changes alter how the invading immune cells function, this may have substantial impact on patient care. We may identify specific metabolic markers that can inform us about the severity of disease and response to treatment. In addition, our findings may reveal new biochemical pathways that could be used as a target for treatment. Given that these pathways would primarily alter the kidney tissue cells and not the immune cells, the hope would be that these treatments would result in fewer side effects and reduce infections by preventing immunosuppression in our lupus patients. This work will ultimately help define new treatments for patients with lupus nephritis. Moreover, due to similar processes that may be shared with other kidney diseases, our findings may contribute to possible new treatments for kidney disease in non-lupus patients. The ultimate goal of this work is to improve patient care and quality of life. Eventually, our goal is to take this work and move our findings from the bench to the bedside. This can be completed in two ways. First, if we identify metabolic pathways that inform us about the disease state of lupus nephritis, diagnostic or prognostic markers could be developed and translated to the clinic in a few years. If our hypothesis is correct, that kidney tissue is metabolically reprogrammed in lupus nephritis, several FDA approved therapies targeting metabolism are available, which may allow for relatively rapid translation of our findings from the bench to the bedside. In all, this study not only has the potential to broaden our current understanding of lupus nephritis, but may lead to novel diagnostic tests and therapies targeting metabolic changes seen in lupus nephritis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910722
Entities
People
- Jeremy Tilstra
Organizations
- United States Army
- University of Pittsburgh