Evaluating the Mechanisms of Afferent Renal Nerve Ablation as a Treatment for Hypertension

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Hypertension (HTN) is one of the most important risk factors for cardiovascular disease. Nearly half of HTN patients are resistant or nonadherent to lifestyle modification and drug-based therapy, so novel therapies are desperately needed. While HTN is associated with increased global sympathetic nerve activity, renal efferent nerves have traditionally been the focus of research since they transmit sympathetic nerve impulses from the brain to regulate blood pressure. However, the kidneys are also innervated by renal afferent (sensory) nerves, which project to circuits in the brain that modulate sympathetic nerve output and cause HTN. Clinical trials using catheter-based total (efferent and afferent) renal nerve ablation (TRDN) have been shown to effectively lower arterial pressure in treatment-resistant HTN patients. Despite this intervention’s efficacy, it is unknown if ablation of the efferent or afferent renal nerves is more important in lowering arterial pressure. To elucidate the role that afferent renal nerves play in HTN, our laboratory developed a novel method of afferent renal nerve ablation (ARDN) and found that ARDN was as effective as TRDN in decreasing arterial pressure in the deoxycorticosterone acetate and high salt diet (DOCA-salt) induced HTN rodent model. Clinically, if ARDN can lower arterial pressure to the same degree as TRDN, efferent renal nerves could be preserved to maintain blood pressure and volume in response to hemorrhagic or septic shock. Furthermore, TRDN has shown variable efficacy in certain patients, and the lack of biomarkers to predict the arterial pressure response to TRDN is a major gap in the field. Recent studies from our lab suggest that the presence of specific inflammatory cytokines in the urine can identify renal inflammation. These cytokines can overstimulate afferent renal nerves and cause increased global sympathetic nerve output and HTN. I plan on translating our findings from DOCA-salt HTN rodents to the DOCA-salt HTN sheep model. The anatomic, physiologic, and hemodynamic properties of HTN sheep more closely resemble human pathophysiology and allows for the use of human TRDN catheters. Therefore, the overall goal of this proposal is to develop and validate a catheter-based ARDN method using the HTN sheep model to address current gaps in the field and move closer to a clinical therapeutic for hypertension. Our central hypothesis is that catheter-based ARDN will decrease arterial pressure to the same degree as TRDN, and the arterial pressure response to TRDN can be predicted by specific urinary markers of renal inflammation. I will test this hypothesis with the following aims: (1) Compare the efficacy of catheter-based ARDN versus TRDN in an established model of HTN in sheep. (2) Validate the utility of urinary biomarkers to measure renal inflammation associated with HTN to predict the anti-HTN efficacy of TRDN. If successful, the results of the proposed studies will provide a translational platform to subsequently move into clinical trials of catheter-based ARDN in humans. Furthermore, this catheter-based neuromodulation approach can also be applied to other organs (liver, spleen) in which chronic inflammation drives other neurogenically based diseases.