Involvement of the Brain (Pro)renin Receptor in Cardiovascular Homeostasis

Abstract

Key Words: (pro)renin receptor Ⅲ supraoptic nucleus Ⅲ cardiovascular homeostasis Ⅲ mean arterial pressure E vidence demonstrates that the renin-angiotensin system (RAS) is intrinsic to the brain and has an integral role in the neural control of cardiovascular functions. 1,2 Despite this, there is ongoing debate about the existence of an intrinsic brain RAS. 1,3 Skeptics have argued that brain levels of renin are too low to have any impact on angiotensin II formation and hence its actions. [3][4][5] In addition, discrepancies in the cellular localization of angiotensinogen, angiotensin-converting enzyme, and angiotensin II type I receptors (AT 1 Rs) have made it difficult to explain the access of angiotensin II to cardiovascular-relevant neuronal circuits. 1 Discovery of (pro)renin receptor (PRR) may be a key to resolving this enigma.PRR is a 350-aa transmembrane protein that binds prorenin or renin with comparable affinity. 6 PRR plays a dual role in the regulation of RAS activity: it binds prorenin/renin to facilitate angiotensin II formation locally; and the binding initiates an intracellular signaling cascade, which is similar to those associated with angiotensin II-mediated increases in pressor, proliferative, and fibrotic actions. 4,6 These observations, coupled with recent data that PRR is highly expressed in cardiovascular-relevant brain regions and affects neurons in vitro, 7,8 have led us to propose the following hypothesis: brain PRR is involved in the regulation of central cardiovascular function and its dysregulation may contribute to hypertension. Our objective in this study was to evaluate this hypothesis.

Water Deprivation Increases (Pro)renin Receptor Levels in the Kidney and Decreases Plasma Concentrations of Soluble (Pro)renin Receptor

“…(P)RR was colocalized with vasopressin in the paraventricular and supraoptic neurons of hypothalamus (Takahashi et al 2010a). Shan et al (2010) showed that (P)RR overexpression in the supraoptic nucleus stimulated vasopressin secretion and chronic knockdown of (P)RR decreased it in rats, suggesting that (P)RR plays a role in vasopressin secretion in the hypothalamus. Hypothalamic (P)RR may therefore modulate the vasopressin secretion against dehydration.…”

Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats

“…The importance of the brain PRR in cardiovascular control is further strengthened by the observation that increased PRR expression in brain cardiovascular control areas altered body fluid homeostasis (38) and genetic knockdown of the PRR induced long-term depressor effects in hypertensive animals (21,22,38). However, the detailed mechanism underlying the role of brain PRR on blood pressure regulation is not well understood.…”

“…Chronic overexpression of this receptor in the SON alters body fluid homeostasis in normotensive rats, while genetic knockdown of the expression of SON PRR significantly attenuated the age-dependent blood pressure increase in the SHR (38), indicating hypothalamic PRR plays a critical role in the control of blood pressure. PRR is also highly expressed in the hypothalamic paraventricular nucleus (PVN) (7,38). The PVN is one of the most important brain areas controlling sympathetic outflow.…”

“…In addition, the PRR-(pro)renin complex stimulates a variety of signal transduction pathways independent of ANG II (8,28,46). Our previous study has shown that PRR is highly expressed in the brain cardiovascular control areas such as the hypothalamic supraoptic nucleus (SON), and its expression is significantly increased in the spontaneous hypertensive rat (SHR) compared with normotensive Wistar-Kyoto (WKY) controls (38). Chronic overexpression of this receptor in the SON alters body fluid homeostasis in normotensive rats, while genetic knockdown of the expression of SON PRR significantly attenuated the age-dependent blood pressure increase in the SHR (38), indicating hypothalamic PRR plays a critical role in the control of blood pressure.…”

Ontogeny of the (pro)renin receptor

“…(P)RR is expressed in the adult brain, where it plays a role in the neural control of cardiovascular functions, regulation of Erk1/2 signaling, and neuron differentiation (5,32). The possibility that (P)RR may be important for brain development is supported by the findings that Xenopus embryos injected with (P)RR antisense morpholino oligonucleotides have small head size (25).…”