Cardiovascular diseases (CVD) remain 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. The central mechanisms involving the lamina terminalis and the paraventricular nucleus of the hypothalamus (PVN) play an important role in the development of SSH; in particular, the angiotensin II (Ang II) type 1 receptor (AT1R) in the PVN mediates elevation 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 PRR promotes Ang II formation and activates Ang II-independent mitogen-activated protein kinases (MAPK) signals. Our preliminary data show that PRR expression levels are elevated in the PVN of hypertensive human subjects, but the significance of this elevation during hypertension is not known. Our central hypothesis is that elevated PRR expression in the PVN contributes to the pathogenesis of SSH by increasing local Ang II formation and enhancing the intracellular MAPK signal activation. To test our hypothesis, we have obtained PRR-floxed mice generated a PRR conditional knockout mouse model (Nefh-PRRKO) by breeding PRR-floxed mice with mice expressing Cre recombinase under the control of neuron-specific neurofilament-H (Nefh) promoter. In this proposal, we will induce SSH in these novel mouse models, combined with PVN micro-injection technique and state-of-the-art telemetry recording to test our hypothesis. Our objective is to delineate the functional importance of PRR signaling pathways in the PVN in SSH, and the epigenetic mechanisms leading to PRR elevation in SSH. The following specific aims will be addressed: 1) Determine if PRR activation in the PVN mediates the development of SSH. 2) Elucidate the contribution of PRR-mediated MAPK signaling in the PVN to SSH. 3) Identify the mechanisms responsible for elevated PRR expression in the PVN in SSH. The proposed research will uncover the role of PVN PRR in SSH and elucidate the underlying signaling mechanisms. The successful completion of these studies will have a significant positive impact on the treatment of SSH by filling the knowledge gap of the importance PRR in SSH and providing a novel therapeutic target.