(Pro)renin receptor as a therapeutic target for the treatment of hypertension?

I t is now well established that the intrinsic brain renin–angio-tensin system (RAS) is an integral constituent of the neural regulatory machinery on cardiovascular functions; hyperactivity of this system contributes to neural mechanisms of hypertension. Whereas all components of the RAS have been identified in the brain, 1 exactly how the bioactive angiotensin II (Ang II) is synthesized from an extremely low level of renin in brain 2 remained for decades a debate. This debate was resolved when the (pro) renin receptor (PRR), a specific receptor for renin and (pro)renin, was discovered in 2002. 3 This discovery prompted a reinvestiga-tion of the brain RAS signaling in cardiovascular homeostasis. PRR is a 350-amino acid protein with a single transmem-brane domain. 3 When bound to (pro)renin, PRR initiates a nonproteolytic activation of (pro)renin that mediates Ang II formation via the classical RAS pathways. In addition, binding of (pro)renin to PPR activates a RAS-independent intracel-lular signal transduction pathway that results in the production of reactive oxygen species, 4 proinflammatory and profibrotic factors, as well as cellular proliferation. 5 Accumulating evidence supports an importance role for brain PRR in local generation of Ang II. Incubation of cultured neuronal cells with human (pro)renin and angiotensino-gen results in augmented generation of Ang I and Ang II. 6 In human neuroblastoma cells overexpressed with human PRR, (pro)renin mediates Ang II formation in a dose-dependent and captopril-reversible manner, confirming the derivation of Ang II from Ang I. 4 Conversely, brain-targeted PRR knock-down using PRR short hairpin RNA significantly decreases Ang II levels in the hypothalamus of human renin and angio-tensinogen double transgenic mice. 7 In addition, both base-line and (pro)renin-induced increase in Ang II levels in the hypothalamus and brain stem are significantly decreased in neuron-specific PRR-knockout mice. 8 Accumulating evidence also supports an important role for brain PRR in neural regulation of blood pressure. Both PRR mRNA and protein are distributed in key brain regions that are involved in the regulation of blood pressure and body fluid homeostasis, with a significant increase in their expressions under hypertensive conditions. A definitive role for brain PRR in neural control of blood pressure was established when gene knock down of brain PRR attenuates Ang II–dependent hypertension, 7 retards age-dependent increase in blood pressure in spontaneously hypertensive rats, 6 and prevents the development of salt-sensitive hypertension. 8 Despite gene knockdown studies established a role for PRR in neural control of blood …