( Pro ) renin Receptor and Vacuolar H - ATPase

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 (acidactivation) 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 with a vacuolar H -ATPase. Consequently, the second name of the protein is ATP6ap2 (ATPase, H transporting, lysosomal accessory protein 2). Vacuolar H -ATPases play important roles in the acidification of intracellular compartments and cellular pH homeostasis,6 eg, in the secretory granules of renin-synthesizing juxtaglomerular cells, where proteases (cathepsin B, prohormone convertases) cleave off the 43-amino acid prosegment to yield renin from prorenin. Vacuolar H -ATPases are expressed in virtually every cell of the body. They consist of many subunits, encoded for by different genes and sometimes having 1 isoform. Although their location is mainly intracellular, they also occur in the membrane of certain cells, including renal intercalated cells, osteoclasts, and macrophages. In the apical membrane of A-type renal intercalated cells, vacuolar H -ATPases function in proton secretion in preurine and, hence, in urinary acidification. Angiotensin II increases the activity of vacuolar H ATPase in renal proximal tubule cells, mainly by increasing the apical plasma membrane expression of vacuolar H ATPase.7 This most likely relates to the observation that the vacuolar H -ATPase B subunit contains binding sites to F-actin so that an interaction between vacuolar H -ATPase and actin filaments allows trafficking between the cytosol and the cell surface. Because the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 inhibited such trafficking,7 it appears that p38 MAPK, after its activation by angiotensin II, plays a role in the control of cytoskeleton proteins. Interestingly, in neonatal rat cardiomyocytes, prorenin also induced stimulation of the p38 MAPK pathway, thereby similarly resulting in alterations in actin filament dynamics.3 This phenomenon occurred both with and without renin-angiotensin system blockers, indicating that it is angiotensin-independent. Apparently, therefore, both prorenin and angiotensin activate actin filament trafficking in a p38 MAPK–dependent manner, and in the case of angiotensin II, this results in cell surface expression of vacuolar H -ATPase, thus increasing apical vacuolar H -ATPase activity. In the present issue of Hypertension, Advani et al8 provide data suggesting that renin and prorenin also increase vacuolar H -ATPase activity, most likely via activation of the (pro) renin receptor. They first demonstrate that the (pro)renin receptor is predominantly expressed in collecting ducts, distal convoluted tubules, and distal tubules. This opposes the early observation by Nguyen et al1 regarding (pro)renin receptor localization in arteries and mesangium. The authors attribute this discrepancy to a difference in the primary antibodies used. Within the collecting ducts, expression was most abundant in microvilli at the apical surface of A-type intercalated cells. Interestingly, the receptor colocalized markedly with the B subunit of vacuolar H -ATPase (overlap coefficient: 0.92). Moreover, in cultured collecting duct/distal tubule lineage Madin-Darby canine kidney cells, both renin and prorenin induced extracellular signal–regulated kinase (ERK) 1/2 phosphorylation, and the selective vacuolar H ATPase inhibitor bafilomycin prevented this activation. This suggests that ERK1/2 phosphorylation in these cells depends on vacuolar H -ATPase activity. Because bafilomycin did not prevent prorenin binding to vascular smooth muscle cells overexpressing the human (pro)renin receptor (Batenburg et al, unpublished observations, 2008), it appears that the increase in vacuolar H -ATPase activity occurs after renin/ prorenin binding to their receptor. Advani et al8 applied The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. 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 [email protected] (Hypertension. 2009;54:219-221.) © 2009 American Heart Association, Inc.