Innate Immune Mediated Changes in Renal Function to Cause Hypertension in Females with Autoimmune Disease

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Primary hypertension is linked with immunological changes, including autoantibody production, that are consistent with autoimmune underpinnings of hypertension. The innate immune response also has a central role in the development of autoimmunity; however, the mechanistic contributions of innate immunity to autoimmune associated hypertension have not been studied. This proposal will examine a novel innate immune feedforward mechanism that promotes hypertension during systemic lupus erythematosus (SLE), a disorder that predominantly affects young women, thus significantly advancing the field towards a better understand of immune mediated hypertension. We previously showed that an experimental female mouse model of human SLE exhibits impaired renal vascular function and sodium handling, renal oxidative stress, and hypertension that is ameliorated by antioxidants. Despite this, little is understood about the cellular sources of reactive oxygen species or the intracellular pathways that drive changes in renal function during SLE associated hypertension. The innate immune response has an important role in causing tissue damage during SLE. This proposal will test the central hypothesis that during SLE there is a feedforward mechanism driving the generation of renal ROS, leading to impaired renal vascular function and increased tubular sodium reabsorption. This cycle involves the presence of NETs that increase cell stress signals, including HMGB1, TLR4 mediated mitochondrial dysfunction, and the production of ROS. Mitochondrial ROS activate the NLRP3 inflammasome, which perpetuates the cycle by promoting further generation of NETs to induce additional cell stress. This will be tested in three aims (1) During SLE, NETs promote hypertension by increasing renal ROS that causes impaired renal vascular and tubular function. (2) During SLE, cell stress proteins (HMGB1) increase mitochondrial ROS generation leading to NLRP3 inflammasome activation and further NET production through a TLR4 mediated mechanism. (3) A large data cohort (approximately 32,000) from men and women with SLE will be examined for relationships between clinical markers of inflammation, immunotherapies, and blood pressure. The proposal uses widely established models of SLE, an innovative genetic model, state-of-the-art physiological, pharmacological, and immunological methods, along with a national data base of human clinical data to rigorously test these aims.