Renal mechanisms of hypertension in autoimmune disease

Veterans Health Administration, Decatur PA

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Abstract

The prevalence of hypertension is markedly increased in patients with autoimmune disorders, and growing evidence links primary hypertension to immunological changes associated with autoimmunity including the production of autoantibodies (IgG). The underlying mechanisms by which autoimmunity contributes to the prevalent hypertension in the general population and U.S. active duty military and veterans remains poorly understood. This proposal will directly advance our understanding of hypertension during autoimmunity, thus narrowing a knowledge gap that will ultimately lead to improved treatment of hypertension not only for U.S. military veterans, but also for patients with primary hypertension. We previously established that 1) an experimental mouse model closely mimics human SLE including the prevalent hypertension with significant renal immune cell infiltration; 2) mice with SLE have impaired renal vascular function and renal sodium handling as an underlying factor in development of hypertension; 3) renal production of reactive oxygen species is increased, and treatment with general antioxidants attenuates the hypertension in mice with SLE; 4) immunosuppressive and anti-inflammatory treatments protect against the development of hypertension during SLE in association with reduced renal oxidative stress; and 5) circulating IgG, a critical pathogenic mechanism of autoimmune diseases, directly contribute to the hypertension in mice with SLE. Taken together, these studies strongly suggest that immune mediated increases in renal oxidative stress is a fundamental mechanism leading to the prevalent hypertension during autoimmunity. Despite this evidence, surprisingly little is understood about the cellular sources of reactive oxygen species in the kidneys, or the intracellular mechanisms that increase renal oxidative stress during SLE. In a preliminary study, we show that renal neutrophils are increased in mice with SLE and that these same mice make IgG to myeloperoxidase, an enzyme essential for the neutrophil oxidative burst and associated with neutrophil extracellular traps (NETs) that are pathogenically linked to autoimmune disease in humans. In addition, we identified IgG raised against mitochondrial antigens, and have preliminary data showing that mitochondrial respiration is impaired, along with increased production of mitochondrial reactive oxygen species. Taken together, these data suggest a central role for IgG, neutrophils and mitochondrial dysfunction in the pathogenesis of autoimmune mediated hypertension. This proposal will examine how NETs and IgG act at the cellular level to cause mitochondrial dysfunction in a feed forward mechanism. We propose that this feed forward mechanism is propagated by IgG mediated activation of FcγR, and the subsequent activation of the NLRP3 inflammasome. Based on our preliminary and published data, our central hypothesis is that during SLE, NETs initiate mitochondrial damage in the kidney that leads to the production of IgG raised to mitochondrial antigens. The autoantibodies bind to FcγR in the kidney and activate the NLRP3 inflammasome, further impairing mitochondrial function. This sets up a feed forward mechanism of mitochondrial ROS generation that causes renal vascular dysfunction and increased sodium reabsorption resulting in increased arterial pressure. Using a clinically relevant experimental model that closely mimics human SLE, this hypothesis will be tested in the following specific aims (1) To test the hypothesis that during SLE neutrophils are important mediators of renal mitochondrial dysfunction and mechanistically contribute to the development of hypertension. (2) To test the hypothesis that during SLE, circulating IgG promotes impaired mitochondrial function through FcγR mediated activation of the inflammasome, leading to ROS generation, impaired renal function and hypertension. These experiments will significantly advance our understanding of the underlying pathology for changes in renal function that cause hypertension both for patients with SLE and for the general population.