Moving Targets

In addition to its well-known role in regulating blood pressure and fluid balance, the renin-angiotensin-aldosterone system (RAAS) has continued to fascinate both researchers and clinicians because of the several additional functions that it has been proposed to carry out. Disruption of the production or action of angiotensin II (Ang II) during development, either by gene mutation or by pharmacological blockade, results in tubular agenesis and anemia in the fetus (humans) or offspring (laboratory animals) and is most often lethal.1,2 Some of the suspected, but still unproven, roles of angiotensin peptides include effects on energy metabolism,3 longevity,4 memory,5 autoimmune diseases,6,7 and a direct, blood pressure–independent effect on tissue damage. This latter role is extremely hard to prove, because the effects of Ang II on blood pressure are hard to separate from its potential direct effects on tissues both in the laboratory and in clinical trials. The most recent developments in RAAS research have led to the suggestion that tissue damage may not be solely attributable to the action of angiotensin peptides but may also involve a direct effect of renin and its protein precursor, prorenin. The concept that prorenin and renin play a direct role in vascular pathologies is largely built on 4 lines of evidence. First is the finding that elevations of circulating prorenin were associated (and may even precede) diabetic microvascular disease.8,9 Second is the report that transgenic rats engineered to have a 400-fold increase in circulating prorenin developed severe cardiac remodeling and renal lesions in the absence of hypertension,10 raising the possibility that prorenin was not only associated with tissue damage but that it may even be responsible for the damage by a mechanism that did not require Ang II generation. Third is the discovery of the so-called (pro)renin receptor ((P)RR), which binds both prorenin and renin with nanomolar affinity,11,12 causes an unfolding of prorenin11,13 rendering it capable of contributing to local Ang II generation, and triggers several mitogen-activated protein kinase (MAPK) signaling pathways11,14–16 on prorenin and renin binding (Figure). Because this MAPK stimulation occurs in the presence of RAAS inhibitors, the triggered signaling appears to be independent of the angiotensin-generating enzymatic activity of prorenin and renin.14,15,17 The fourth major line of support came from a series of experiments suggesting that inhibiting the binding of renin and prorenin to (P)RR with a competing peptide called handle region peptide (HRP; later also called prorenin receptor blocker or PRRB; see Figure) reduced cardiac hypertrophy and fibrosis in hypertensive rats without reducing blood pressure,18 reduced diabetic glomerulosclerosis and proteinuria in rats19 and in mice in which the Ang II type 1 (AT1) receptor had been inactivated,20 and reduced pathological, but not physiological, retinal neovascularization.21 Altogether, these data have led to a model in which renin and prorenin, through their interaction with (P)RR, stimulate a signal other than Ang II that promotes cardiac remodeling, microvascular damage, and retinal neovascularization. Not surprisingly, these reports have stirred the hope that new and more effective treatments could be developed to prevent secondary organ damage in hypertension and diabetes mellitus by blocking the action of renin or prorenin on (P)RR. It is also important to revisit the key findings that brought us to this new hope, because these 4 lines of evidence have been severely tested in the last couple of years. Where do we stand today?