Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality despite recent advances in pharmacological therapy and acute patient care. Hypertension is the major risk factor for CVD and contributes to 95% of CVD deaths. Salt-sensitive hypertension (SSH) is a major form of human primary hypertension. Central mechanisms involving the lamina terminalis and the paraventricular nucleus (PVN) of the hypothalamus play an important role in the development of SSH. In particular, the angiotensin II (Ang II) type 1 receptor (AT1R) in the PVN mediates increases in sympathetic tone and blood pressure (BP) in response to high salt. The (pro)renin receptor (PRR) is a newly discovered component of the renin-angiotensin system (RAS). Binding of renin or prorenin to the PRR promotes Ang II formation and also activates Ang II- independent mitogen-activated protein kinase (MAPK) signaling. Our preliminary data show that PRR expression levels are elevated in the PVN of hypertensive human subjects; however, the significance of this elevation during hypertension is not known. Our central hypothesis is that hypertensive stimuli increase PRR expression epigenetically in the PVN, which promotes local Ang II formation through activation of prorenin, leading to sympathoexcitation and hypertension. To test this hypothesis, we will apply PVN microinjection and telemetry recording techniques to a mouse model of experimentally SSH. Central to these studies is a PRR conditional knockout mouse strain (Nefh-PRRKO) that we generated by breeding mice expressing Cre recombinase under the control of a neuron-specific neurofilament-H (Nefh) promoter, produced in our laboratory, with PRR-floxed mice. Our objectives are to delineate the functional importance of PRR signaling pathways in the PVN in hypertension and elucidate the epigenetic mechanisms leading to PRR elevation. The following specific aims will be addressed: 1) Test the hypothesis that PRR activation in the PVN mediates the development of hypertension. 2) Test the hypothesis that mitogen-activated protein kinase signaling downstream of the PRR is mandatory for the development of hypertension. 3) Identify the epigenetic mechanisms responsible for elevated PRR expression in the PVN in hypertension. The proposed research will uncover the role of the PVN PRR in hypertension and elucidate the underlying signaling mechanisms. By establishing the importance of the PRR in hypertension and describing novel therapeutic targets, these studies will have a direct impact on cardiovascular biology and may open the door to the development of a new category of antihypertensive drugs.
Hypertension affects approximately 74 million people in the United States, but about 40% of these patients fail to achieve adequate blood pressure control with standard therapies. The body's mechanisms for regulating blood pressure are not understood in their full complexity. Successful completion of these studies on the role of the (pro)renin receptor is expected to provide key insight into blood pressure regulation mechanisms and facilitate the development of novel antihypertensive drugs.
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