Renal Sensory Nerve Contribution to Hypertension

PROJECT SUMMARY/ABSTRACT:
High blood pressure is a leading cause of morbidity and mortality worldwide and greatly contributes to a
multitude of cardiovascular disease. Although the renal sympathetic nerves have been the focus of many basic
and clinical studies, the role of the renal afferent (sensory) nerves in mediating hypertension remains poorly
understood. Activation of renal afferents can potentially either excite or inhibit global sympathetic nerve activity
and thereby increase or decrease blood pressure, but the precise mechanisms controlling the balance of the
excitatory vs. inhibitory reflex actions of the renal afferent nerves are currently unknown. We have recently
determined that the endothelin-1 (ET-1) system significantly modulates renal afferent nerves. Our central
hypothesis is that endothelin A (ETA) receptor activation on renal afferent nerves increases sympathetic
nerve activity and blood pressure, and that endothelin B (ETB) receptor activation on renal afferent
nerves decreases sympathetic nerve activity and blood pressure. We will test this hypothesis using rodent
models in the settings of both normal physiology and hypertension. ETA or ETB receptors on renal nerves will be
directly activated in rats instrumented with radiotelemetry devices, which allow for recording of blood pressure
and markers of sympathetic nerve activity in unrestrained, conscious animals. These experiments, which will
also include in vitro culturing, imaging, and electrophysiological examination of renal afferent nerves will provide
important new information about the mechanisms of afferent nerve activation.
High salt and high fat content are common features of the typical Western diet and are well-known to
play a role in the development of many cardiovascular diseases such as hypertension. Our preliminary evidence
indicates that these factors also increase renal afferent nerve expression of ET-1 and ETA receptors. Because
of this connection to increases in abberant renal afferent nerve activity and blood pressure, we will also test the
hypothesis that high salt or high fat diet increases afferent nerve ET-1 expression and a preponderance
of ETA to ETB receptor signaling promoting increased afferent nerve activity, sympathetic tone, and blood
pressure. This hypothesis will be tested through the use of rat models with specific pharmacological inhibition
of ETA and/or ETB receptors on renal afferent nerves, and animals will be fed a high salt or high fat diet.
Together, these studies will provide a mechanistic understanding of how excitation versus inhibition of
renal afferent nerves contributes to hypertension and thus could lead to specific and efficient therapeutic
interventions for the treatment of hypertension. This research study and the proposed mentored training plan will
provide the applicant with the specific scientific training needed for successful transition into independence.

Grant Number: 5K01HL159047-05
NIH Institute/Center: NIH
Principal Investigator: Bryan Becker