The renin–angiotensin system

The development of the first peptide angiotensin-converting enzyme inhibitor in the 1970s [1] represents a major milestone in the history of the treatment of hypertension. Since this time, the renin–angiotensin system (RAS) has become a cornerstone in strategies to treat hypertension and reduce cardiovascular risk clinically. However, cardiovascular disease remains a leading cause of death and disability worldwide; although major clinical trials have refined and changed treatment approaches over the last decade, significant advances have not been forthcoming. Effective preventive measures require a clearer understanding of the factors that initiate and ‘set’ long-term changes in arterial pressure control. The RAS is a major regulator of cardiovascular and renal function. Classically, the RAS, via the actions of angiotensin II (AngII) at the angiotensin type-1 receptor (AT1R) causes vasoconstriction, renal sodium retention, vascular growth and inflammation. It has been firmly established that the RAS plays a role in the pathophysiology of hypertension; however, the precise mechanisms remain elusive. This is in part because specific defects in the RAS have not been definitely linked to the cause of essential hypertension, perhaps because our understanding of the RAS has been simplistic. However, in recent years, ancillary components of the RAS have been identified, including active AngII peptide fragments, receptors, enzymes and G protein-coupled receptor interacting proteins [2,3]. Thus, our view of the RAS has expanded and now the interactions between these pathways are being intensively explored in the context of hypertension and cardiovascular disease. The study of Dejima et al. [4], in this issue of the Journal of Hypertension, demonstrates that prepubertal angiotensin receptor blockade (ARB) attenuated the increase in arterial blood pressure in Dahl salt-sensitive rats following the administration of a high-salt diet and that this difference in arterial pressure was maintained following withdrawal of the ARB. This work recapitulates earlier work demonstrating that short-term treatment, in early life, with an angiotensin-converting enzyme inhibitor or ARB persistently lowers arterial pressure in the spontaneously hypertensive rat [5–10] and the Dahl salt-sensitive rat fed a high-salt diet [11]. This effect is unique to these drugs, as other classes of antihypertensive agents, β-blockers, vasodilators and calcium antagonists do not persistently lower arterial pressure when treatment is stopped [5,11]. The fact that the maintenance of arterial pressure lowering, following drug removal, is associated with all drugs that inhibit the RAS suggests an involvement of this important homeostatic system in the development of hypertension, although the mechanistic pathway has not been established. To this end, Dejima et al. demonstrated that renal AT1R-associating protein (ATRAP) expression, which was decreased in Dahl salt-sensitive rats fed a high-salt diet, was restored with ARB treatment and that this increase in ATRAP was maintained following the withdrawal of the ARB. Furthermore, this upregulation of ATRAP was associated with a reduction in markers of renal markers of oxidative stress, inflammation and fibrosis. These results suggest that ATRAP suppresses the pathophysiological effects of AT1R activation. This study is one of a series of experiments that Dejima et al. have performed that examines the role of ATRAP under various conditions. ATRAP is an accessory protein that specifically interacts with the AT1R and is expressed in aorta, kidney and heart [12]. ATRAP decreases membrane localization of the AT1R following Ang II stimulation by promoting AT1R internalization [13,14]. Cardiac-specific overexpression of ATRAP has been demonstrated to prevent AngII-induced cardiac hypertrophy [15]. Other workers have also supported a role for ATRAP in the modulation of the RAS and the regulation of arterial pressure, with ATRAP knockout mice being shown to have increased arterial pressure and plasma volume [16]. Thus, ATRAP has the potential to regulate the physiological response to AngII stimulation. Understanding contribution of ATRAP and other ancillary components of the RAS and their interactions will in future lead to a greater understanding regulation of extracellular fluid volume and arterial pressure by the RAS, which may lead to improved treatments. The potential role of microRNAs in the translational repression or destabilization of RAS gene regulation [17] will also add another level of complexity in the unraveling the role of RAS in hypertension and cardiovascular and renal disease. Moreover, it is apparent that there are significant sex-differences in the regulation of arterial pressure by the RAS [18,19], which likely contribute to the lower incidence of cardiovascular disease in women. Therefore, the impact of estrogen and testosterone on these new RAS pathways and potential regulatory mechanisms should be explored if we are to open up new opportunities for pharmacological regulation of RAS activity. Finally, it is noteworthy that Dejima et al., and previous studies [5–10], have demonstrated that the pre-pubertal window may be particularly important in achieving long-term arterial pressure lowering effects. This suggests that the postnatal period is a critical window in the programming of hypertension [20] and may be a target for interventions in the future. Acknowledgements Conflicts of interest There are no conflicts of interest.