Characterization of a functional (pro)renin receptor in rat brain neurons.

Recent discovery of (pro)renin receptor (PRR) has revolutionized the field of renin–angiotensin system (RAS) physiology and has underscored the critical role of the local and tissue RAS in the development and establishment of cardiac, vascular and renal pathophysiology linked to hypertension and diabetes (Ichihara et al. 2007; Nguyen, 2007). (Pro)renin receptor is a 350 amino acid protein with a single transmembrane domain that binds and actives prorenin. Prorenin contains a ‘handle’ region that conceals the active site of renin (Suzuki et al. 2003). Prorenin binding to PRR results in non-proteolytic activation of the enzyme by inducing a conformational change at the ‘handle’ region, exposing the active site (Nguyen et al. 2002; Danser et al. 2007). In addition, renin binding to the PRR increases its intrinsic activity. Thus, prorenin bound to PRR is many-fold more efficient in the conversion of angiotensinogen to angiotensin I, subsequently leading to increased angiotensin II (Ang II) at the tissue level (Nguyen et al. 2002; Nguyen, 2007). Studies have established that PRR plays a dual role in the regulation of RAS activity: it binds to prorenin/renin to facilitate the formation of Ang I and II, and the binding initiates an intracellular signal transduction pathway involving mitogen-activated protein kinases (MAPK). The latter action is presumably associated with increased synthesis of profibrotic molecules such as plasminogen activator inhibitor-1 (PAI-1), fibronectin, collagen and transforming growth factor-β (TGF-β; Huang et al. 2006; Danser et al. 2007; Nguyen, 2007). The importance of PRR in the cardiovascular system is further evident from pathophysiological and transgenic studies. For example: (i) inhibition of PRR by a ‘handle’ region peptide has been shown to protect the heart and kidney against tissue damage induced by hypertension (Ichihara et al. 2004, 2006); (ii) activation of PRR selectively promotes pathological retinal neovascularization (Satofuka et al. 2007); and (iii) overexpression of PRR in rats results in elevated blood pressure and increased plasma aldosterone (Burckle et al. 2006). Collectively, these observations indicate that PRR may be a critical member of the RAS in the maintenance of normal cardiovascular physiology. In spite of its emerging involvement and importance in cardiac, renal and vascular pathophysiology, nothing is known about the role of PRR in the brain. This is particularly relevant in view of the fact that the brain RAS is integral in neural control of cardiovascular functions and its hyperactivity is linked to hypertension (Veerasingham & Raizada, 2003; Peterson et al. 2006; Osborn et al. 2007). Although the presence of all the components of the RAS is unquestionable in the brain, their cellular distribution and the interplay of different cell types (neurons, glia, etc.) in the generation of Ang II and the access of this hormone to the Ang II type 1 (AT1) receptor in cardiovascular-relevant neurons remains elusive. In addition, the presence of low levels of renin in the brain has been a consistent enigma in establishing an independent role of the brain RAS (Dzau et al. 1986; Baltatu et al. 1998). Discovery of the PRR is of great significance in this regard and may be critical in solving the puzzle of an intrinsic RAS in the brain and delineating the mechanism of neuronal Ang II actions. Thus, our objective in the present study was to determine whether neurons within the brain express a functional PRR, in at attempt to elucidate the role of the brain RAS in cardiovascular functions.