Despite recent advances in pharmacological therapy and patient care, cardiovascular disease (CVD) remains a leading cause of morbidity and mortality. Salt-induced hypertension (SH) is a major form of human primary hypertension, which is the main risk factor for CVD. This proposal is designed to elucidate neural mechanisms underlying SH, with a focus on uncovering novel mechanisms involved in activating the brain (pro)renin receptor (PRR) and renin-angiotensin system (RAS). Accumulating evidence underscores the importance of neural mechanisms in SH, especially the centrality of brain RAS activity in the lamina terminalis and the paraventricular nucleus (PVN) of the hypothalamus. We recently reported that up-regulation of the PRR in the PVN is responsible for increased angiotensin II production, activation of the brain RAS and the development of SH, suggesting that the PRR is a key link in the chain leading from high-salt intake to brain RAS activation. However, how a high-salt diet up-regulates the brain RAS and PRR remains unknown. Our central hypothesis is that high salt up-regulates the brain PRR through an epithelial sodium channel (ENaC) and reverse mode Na+/Ca2+ exchanger (rNCX)?coupled signaling pathway, and modifies the central nervous system epigenetically, leading to the development of SH. To test this hypothesis, we will employ two commonly used mouse models of experimental SH, in conjunction with innovative techniques, including ex vivo live Ca2+ imaging, ground-state depletion followed by individual molecule return (GSDIM) super-resolution microscopy, cell-specific PVN targeting, and telemetry recording of phenotypes in vivo . Our objectives are to define the molecular signaling events that lead to regulation of the brain RAS and to establish the functional significance of epigenetics in SH. The following specific aims are proposed to address these objectives: (1) to test the hypothesis that formation of ENaC-rNCX?coupled subcellular Ca2+ microdomains is responsible for up-regulation of the neuronal PRR in salt-induced hypertension, and (2) to test the hypothesis that H3K4 trimethylation of the PRR promoter is crucial for the development of salt-induced hypertension. The proposed research is conceptually innovative and highly significant because it will resolve the enigma of how high salt intake activates the brain RAS and epigenetically modifies the PRR, leading to the development of SH. Successful completion of this proposal will establish molecular mechanisms of SH involving brain RAS activation and provide mechanistic insight into the epigenetics of hypertension.
Hypertension is an important risk factor for cardiovascular diseases that affects one-third of adults in the United States. How the body regulates blood pressure is not fully understood, but may include epigenetic mechanisms involving interactions of genes with their environment. Successful completion of these studies on the epigenetic mechanisms of hypertension is expected to provide key insight into mechanisms that regulate blood pressure and facilitate the development of novel antihypertensive drugs.
|Peng, Hua; Jensen, Dane D; Li, Wencheng et al. (2018) Overexpression of the neuronal human (pro)renin receptor mediates angiotensin II-independent blood pressure regulation in the central nervous system. Am J Physiol Heart Circ Physiol 314:H580-H592|
|Trebak, Fatima; Li, Wencheng; Feng, Yumei (2018) Neuronal (pro)renin receptor regulates deoxycorticosterone-induced sodium intake. Physiol Genomics 50:904-912|
|Romanick, Samantha S; Ulrich, Craig; Schlauch, Karen et al. (2018) Obesity-mediated regulation of cardiac protein acetylation: parallel analysis of total and acetylated proteins via TMT-tagged mass spectrometry. Biosci Rep 38:|
|Cooper, Silvana G; Trivedi, Darshan P; Yamamoto, Rieko et al. (2018) Increased (pro)renin receptor expression in the subfornical organ of hypertensive humans. Am J Physiol Heart Circ Physiol 314:H796-H804|
|Lu, Xiaohan; Wang, Fei; Xu, Chuanming et al. (2016) Soluble (pro)renin receptor via ?-catenin enhances urine concentration capability as a target of liver X receptor. Proc Natl Acad Sci U S A 113:E1898-906|
|Pitra, Soledad; Feng, Yumei; Stern, Javier E (2016) Mechanisms underlying prorenin actions on hypothalamic neurons implicated in cardiometabolic control. Mol Metab 5:858-68|
|Xu, Quanbin; Jensen, Dane D; Peng, Hua et al. (2016) The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure. Pharmacol Ther 164:126-34|
|Xia, Huijing; de Queiroz, Thyago Moreira; Sriramula, Srinivas et al. (2015) Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress. Am J Physiol Regul Integr Comp Physiol 308:R370-8|
|Wang, Fei; Lu, Xiaohan; Liu, Mi et al. (2015) Renal medullary (pro)renin receptor contributes to angiotensin II-induced hypertension in rats via activation of the local renin-angiotensin system. BMC Med 13:278|
|Li, Wencheng; Sullivan, Michelle N; Zhang, Sheng et al. (2015) Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension. Hypertension 65:352-61|
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