Is (Pro)Renin Receptor a Multifunctional Receptor?

Abstract

The existence of various components of the renin-angiotensin system in the eye has been known for more than a decade, and the importance of this system in ocular pathophysiology is a subject of active investigation.1 It has long been recognized that prorenin, an inactive precursor of renin, is elevated in the ocular fluids of patients with diabetic retinopathy.2 However, the pathophysiological implications of these elevated levels remained a mystery until the discovery of a specific receptor for renin and prorenin: the (pro)renin receptor [(P)RR].3 (P)RR is a 350–amino acid transmembrane protein which has been proposed to function by two distinct mechanisms: (1) by binding to (pro)renin, (P)RR activates renin’s enzymatic activity inherent in prorenin, leading to the generation of angiotensin II by a traditional renin-angiotensin system pathway at the cell/tissue level4; and (2) (pro)renin binding to (P)RR initiates a cascade of signaling events that are associated with profibrotic and proliferative actions, independent of angiotensin II.4 Although the action of (P)RR in the generation of Ang II is documented, its coupling to signaling pathways leading to vasodeleterious effects remains to be fully elucidated. This is, in part, due to lack of a reliable and selective (P)RR antagonist. A peptide segment corresponding to amino acids 10 to 19 of the prorenin prosegment, called handle region peptide (HRP), has gained significant interest as a (P)RR antagonist. HRP has been shown to inhibit prorenin binding to (P)RR, and thus nonproteolytic activation,5 and to be capable of preventing …