Published online before print June 22, 2009, doi: 10.1161/HYPERTENSIONAHA.109.135236
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(Hypertension. 2009;54:219.)
© 2009 American Heart Association, Inc.
Editorial Commentaries |
(Pro)renin Receptor and Vacuolar H+-ATPase
From the Division of Pharmacology, Vascular and Metabolic Diseases, and Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.
Correspondence to A.H. Jan Danser, Division of Pharmacology, Vascular and Metabolic Diseases, Department of Internal Medicine, Room EE1418b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, the Netherlands. E-mail a.danser@erasmusmc.nl
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
The discovery of a "(pro)renin receptor"1 has renewed the interest in prorenin, the inactive precursor of renin. Prorenin binding to this receptor allows prorenin to display enzymatic activity without the accompanying cleavage of the prosegment that normally occurs in the kidney when prorenin is converted to renin. The underlying concept is that binding to the (pro)renin receptor induces a conformational change in the prorenin molecule, involving unfolding of the propeptide from the enzymatic cleft so that the cleft is now accessible to angiotensinogen ("nonproteolytic activation" of prorenin). Similar conformational changes occur at low pH (acid-activation) and low temperature (cryoactivation), but whether these phenomena are of physiological relevance is uncertain. In contrast, the (pro)renin receptor provides a physiological role for prorenin, explaining how angiotensin production might occur at the tissue level and putting into perspective the relatively high prorenin levels (10-fold those of renin) in the human circulation. These levels are even higher in diabetes mellitus complicated by retinopathy and nephropathy.2
Unexpectedly, prorenin binding to its receptor also induces intracellular signaling,1,3 independent of angiotensin generation, suggesting that prorenin may act as an agonist of the receptor. Although similar observations were made on renin, prorenin binds with higher affinity to the receptor and, thus, appears to be its endogenous agonist.4
The (pro)renin receptor is a 350-amino acid protein with a single transmembrane domain. Although it was first identified on cultured human mesangial cells,1 the C-terminal part of the receptor had been described earlier by Ludwig et al5 as an 8.9-kDa fragment associated
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