Neuroimmune Mechanisms Involved in the Pathogenesis of Hypertension and Renal Injury

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PROJECT SUMMARY Hypertension is one of the most prevalent disease processes in the US and, while it undoubtedly has a multifactorial etiology, recent studies support a prominent role for the immune system and chronic inflammation. It is critical that we understand mechanisms that may regulate this inflammation in order to identify new therapeutic targets. The novel cholinergic anti-inflammatory pathway and the established hypothalamic-pituitary-adrenal (HPA) axis are thought to suppress inflammation upon activation. Stimulation of both of these endogenous mechanisms may occur through the parasympathetic vagus nerve. To study whether this neuro-immune crosstalk is important in preventing the development of chronic inflammation that can promote hypertension, we utilize the disease model systemic lupus erythematosus (SLE). SLE is a chronic autoimmune inflammatory disorder characterized by a high prevalence of hypertension, which may be mediated by chronic renal vascular and parenchymal inflammation. Studies have demonstrated that SLE patients have decreased heart rate variability, which indicates impaired autonomic function. Specifically vagal nerve activity is depressed and this correlates with SLE disease severity. It is not known whether this decreased vagal nerve activity contributes to an impaired cholinergic anti-inflammatory pathway and HPA axis dysregulation in SLE, nor whether these potential relationships contribute substantially to the pathogenesis of hypertension in the setting of SLE. The proposed studies utilize an integrative physiological approach, complemented by neurophysiological and immunological techniques, to determine whether vagal dysfunction contributes to the development of chronic inflammation and consequently hypertension in SLE mice. Dr. Keisa Mathis has developed a plan along with her primary mentor, Dr. Steve Mifflin, to conduct the studies proposed within this grant application. Dr. Mathis will add to her current laboratory expertise by receiving training from members of her mentoring team in both neurophysiological (Drs. Mifflin and Cunningham) and immunobiological (Drs. Harrison and LaMarca) techniques. The mentoring team will give guidance on how to use her acquired tools to answer the important questions proposed in this grant and future grants. Dr. Mathis will also gain valuable insight into the interpretation of her data and manuscript/grant preparation. Taken together, this proposal is a coordinated effort to allow Dr. Mathis to refine her skills and to expose her to a new set of skills that she can use to establish herself as a leader in the field of hypertension.