The Role of the (Pro)renin Receptor in Hypertensive Disease.

Tissue angiotensin generation depends on the uptake of circulating (kidney-derived) renin and/or its precursor prorenin (together denoted as (pro)renin). Since tissue renin levels are usually higher than expected based upon the amount of (renin-containing) blood in tissue, an active uptake mechanism has been proposed. The (pro)renin receptor ((P)RR), discovered in 2002, appeared a promising candidate, although its nanomolar affinity for renin/prorenin is many orders of magnitude above their levels in blood. This review discusses (P)RR-related research since its discovery. First, encouraging in vitro findings supported detrimental effects of (pro)renin-(P)RR interaction, even resulting in angiotensin-independent signaling. Moreover, the putative (P)RR blocker "handle region peptide" (HRP) yielded beneficial effects in various cardiovascular animal models. Then doubt arose whether such interaction truly occurs in vivo, and (P)RR deletion unexpectedly turned out to be lethal. Moreover, HRP results could not be confirmed. Finally, it was discovered that the (P)RR actually is a component of vacuolar-type H(+)-ATPase, a multisubunit protein found in virtually every cell type which is essential for vesicle trafficking, protein degradation, and coupled transport. Nevertheless, selective (P)RR blockade in the brain with the putative antagonist PRO20 (corresponding with the first 20 amino acids of prorenin's prosegment) reduced blood pressure in the deoxycorticosteroneacetate (DOCA)-salt model, and (P)RR gene single nucleotide polymorphisms associate with hypertension. To what degree this relates to (pro)renin remains uncertain. The concept of (P)RR blockade in hypertension, if pursued, requires rigorous testing of any newly designed antagonist, and may not hold promise given the early death of tissue-specific (P)RR knockout animals. © American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.