Inflammation-Driven Metabolic Reprogramming in Lupus Nephritis: Podocyte Injury and Rescue by Metabolite Supplementation

Background: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), affecting approximately 50% of individuals with SLE. It is associated with increased morbidity and mortality compared to SLE patients without LN. Podocyte injury is an early and critical event in the pathogenesis of LN; however, the role of alterations in podocyte metabolism remains poorly understood. This study aims to investigate metabolomic changes in the serum of LN patients and their impact on podocytes. Methods: Serum metabolomic profiles were analyzed using liquid chromatography-mass spectrometry (LC-MS) from healthy controls, SLE patients, and LN patients. Human podocytes were exposed to serum samples from healthy, SLE, LN, and LN-remission patients, and gene expression changes were assessed to evaluate the pathogenic effects of patient serum on podocytes. Findings were validated through Seahorse metabolic assays, droplet digital PCR (ddPCR), ATP quantification, and gene expression analyses. Results: Our results indicate that SLE and LN patients exhibit distinct metabolomic signatures in their serum (Healthy vs. SLE: 61 metabolites significantly altered; SLE vs. LN: 80 metabolites significantly altered). Exposure of human podocytes to serum from these patients alters the signaling (IL6, IL1B, NLRP3, CAMK4) and metabolic profile of the podocytes. Several metabolites were found to be significantly up- or down-regulated in the serum of LN and SLE patients, potentially affecting podocyte bioenergetics and contributing to podocyte injury and effacement. Additionally, we observed signs of metabolite depletion in the serum of LN patients. Replenishing the deficient metabolites in vitro partially reversed the detrimental effects of LN serum on podocytes. Conclusion: Our study demonstrates that patients with SLE and LN have significantly altered serum metabolite profiles, which can adversely affect podocytes. Replenishment of specific metabolites may mitigate podocyte inflammation and injury, offering potential therapeutic strategies for LN. Funding: Other NIH Support - Department of Defense, Other U.S. Government Support, Private Foundation Support