Renal hemodynamic mechanisms of hypertension during autoimmunity

Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting an estimated 1.5 million Americans. Hypertension, a cardiovascular risk factor, is prevalent in this patient population, and renal disease is a common manifestation of the disorder. Patients with active flares or advanced renal disease can have impaired renal hemodynamic function including reduced glomerular filtration rate (GFR) and estimated renal plasma flow (RPF). While it is widely established that immune system activation contributes to the pathogenesis of hypertension and that the kidneys have a central role in long term blood pressure control, the impact of autoimmunity on renal hemodynamic function as a mechanism contributing to the pathogenesis of hypertension is unclear. Little is known about the changes in renal hemodynamic function that are likely to mechanistically underlie the development of hypertension during SLE. Our laboratory reported that a clinically relevant experimental mouse model of SLE (female NZBWF1 mice) has reduced renal blood flow and hypertension when the renal injury is advanced. However, it is unknown if autoimmunity induced changes in GFR and RPF precede the increased blood pressure, and occurs prior to the development of renal injury. While the contribution of the adaptive immune system (including autoantibodies, B and T lymphocytes) and inflammatory cytokines like TNF-alpha to the renal disease associated SLE is well known, their role in causing impaired renal hemodynamic function is unclear. Whether suppressing immune system function attenuates the development of hypertension by preserving GFR and RPF has not been tested. The central hypothesis of this proposal is that the loss of immunological tolerance and subsequent production of autoantibodies in SLE leads to impaired renal hemodynamic function that causes hypertension and will be tested utilizing female NZBWF1 mice in the following aims: 1.To test the hypothesis that B and T lymphocyte mediated autoantibody production and TNF-alpha precedes reductions in GFR and RPF during SLE, that subsequently promote the development of hypertension. 2.To test the hypothesis that temporal immunosuppressant therapy with MMF or blockade of TNF-alpha with etanercept attenuates hypertension during SLE by depleting autoantibodies, B and T lymphocytes (MMF) and ROS (etanercept), which preserves GFR and RPF. (AHA Program: Predoctoral Fellowship)