High blood pressure (hypertension; HTN) continues at epidemic levels in the United States. Though HTN etiology remains debated, the kidney remains a key contributor to blood pressure control. Moreover, elevated sympathetic nerve activity (SNA) and innervation of the kidney is closely linked to BP control, through both efferent (signal from brain to kidney) and afferent (kidney to brain) nerve signaling. A large body of experimental and clinical studies demonstrates ablation of these nerves, or renal denervation (RDNx), can prevent and reverse HTN. Although this anti-HTN response is exciting, the mechanism by which RDNx treats HTN remains ill-defined. It remains unclear whether efferent (signal from brain to kidney; ERN) and afferent (kidney to brain; ARN) renal nerves populations differentially contribute to HTN. In general, ERNs regulate renin release, vascular resistance, and sodium excretion, whereas ARNs modulates arginine vasopressin (AVP) secretion and peripheral SNA. Renal nerves are known to interact with and influence renal inflammation (nephritis), which is posited to cause HTN. Consistent with these findings, our laboratory has recently demonstrated the antihypertensive response to RDNx may be due to the blockade of the interaction between inflammatory signaling and renal nerves. Specifically, we observed ablation of all renal nerves (T-RDNx; efferent+afferent) attenuated HTN and abolished renal inflammatory cytokines (e.g. IL-1?, IL-6, MCP-1) in the DOCA-salt rat model; however, selective ablation of ARNs (A-RDNx) only attenuated the HTN and not the cytokines. DOCA-salt HTN and nephritis was also paired with a 2.3-fold increase in resting afferent renal nerve activity (ARNA) compared to normotensive controls. In concert, these data suggest ERNs regulate inflammatory trafficking, and ARNs mediate the HTN in this model. With our previous observations and strong preliminary data outlined in this proposal, we formed the following testable Central Hypothesis: (a) Elevated renal SNA (RSNA) drives the infiltration of activated immune cells (e.g. T-cells, macrophage) which produce pro-inflammatory cytokines; (b) These cytokines activate or hypersensitize ARNs; (c) Increased ARNA reflexly raises peripheral SNA and AVP release, and, in turn, blood pressure. We will test this hypothesis with the following specific aims: (1) Asses the chronic renal SNA response to DOCA-salt, and the effect of afferent-specific denervation (A-RDNx). We will directly measure ARNA and renal SNA changes in parallel to blood pressure in the DOCA-salt rat. (2) Evaluate if renal inflammation alters renal afferent nerve activity and sensitivity. Using an established in vivo and a novel ex vivo method to acutely measure ARNA, we will determine if renal inflammatory cytokines increase resting ARNA. (3) Determine the role of afferent renal nerves in the regulation of the neurohumoral response to DOCA-salt. We will determine if A-RDNx blunts AVP secretion in the DOCA-salt HTN model. By defining the specific role of renal nerves in HTN and nephritis, we will fundamentally redefine the mechanistic basis for clinical use of RDNx and potentially identify therapeutic targets for the HTN treatment.
High blood pressure (i.e. hypertension) is the single greatest risk factor for cardiovascular disease, which is the leading cause of morbidity and mortality in the United States. Excessive activation of the sympathetic nervous system, particularly to the kidney, plays a large role in hypertension and may be a target for therapy or prevention. The proposed research will aid in the development and refinement of new therapies that target the nerves to the kidney to treat hypertension and related kidney diseases.
