PROJECT SUMMARY:
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-1ß, 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.