Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Cardiol. Mar 26, 2011; 3(3): 72-83
Published online Mar 26, 2011. doi: 10.4330/wjc.v3.i3.72
Renin and cardiovascular disease: Worn-out path, or new direction
Gaurav Alreja, Jacob Joseph
Gaurav Alreja, Jacob Joseph, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, United States
Jacob Joseph, Cardiology Section (111), VA Boston Healthcare System, West Roxbury, MA 02132, United States
Jacob Joseph, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, United States
Author contributions: Alreja G reviewed the literature and wrote the article; Joseph J reviewed the literature and revised the article.
Supported by (in part) a research grant from Novartis Pharmaceuticals to Joseph J
Correspondence to: Jacob Joseph, MD, Cardiology Section (111), VA Boston Healthcare System, 1400 VFW Parkway, West Roxbury, MA 02132, United States. jjoseph16@partners.org
Telephone: +1-857-2035111 Fax: +1-857-2035549
Received: January 15, 2011
Revised: March 2, 2011
Accepted: March 9, 2011
Published online: March 26, 2011


Inhibition of the renin angiotensin system has beneficial effects in cardiovascular prevention and treatment. The advent of orally active direct renin inhibitors adds a novel approach to antagonism of the renin-angiotensin system. Inhibition of the first and rate-limiting step of the renin angiotensin cascade offers theoretical advantages over downstream blockade. However, the recent discovery of the (pro)renin receptor which binds both renin and prorenin, and which can not only augment catalytic activity of both renin and prorenin in converting angiotensinogen to angiotensin I, but also signal intracellularly via various pathways to modulate gene expression, adds a significant level of complexity to the field. In this review, we will examine the basic and clinical data on renin and its inhibition in the context of cardiovascular pathophysiology.

Key Words: Renin, Angiotensin, Cardiovascular disease, Renin receptor, Prorenin receptor


A link between the kidney and left ventricular hypertrophy was reported by Richard Bright as early as 1836[1], and was followed by the studies of Tigerstedt and Berman, who reported on the pressor effects of renal extracts and named the putative pressor renin in recognition of the organ of origin[2,3]. Thus began the saga of the renin-angiotensin system (RAS) and its role in cardiovascular disease (CVD), a role which continues to evolve. A century of research has revealed that the RAS plays an important role in the regulation of blood pressure and the development of hypertension, atherosclerosis, heart failure, type 2 diabetes mellitus and renal disease[4]. Renin is the first and rate limiting enzyme of the RAS cascade which leads to the production of various metabolites which function as key regulators of blood pressure, vascular tone, and salt and water balance, of which angiotensin II (Ang II) is the most studied (Figure 1). Current strategies to inhibit RAS for cardiovascular benefit include angiotensin converting enzyme (ACE) inhibitors, which block the conversion of angiotensin I (Ang I) to Ang II, and angiotensin receptor blockers (ARBs), which prevent the actions of Ang II, specifically on the angiotensin type 1 receptor, the receptor responsible for key adverse cardiovascular effects of Ang II (Figure 1). Both ACE inhibitors and ARBs are established antihypertensive agents, and have beneficial effects in systolic heart failure, atherosclerotic disease, diabetic nephropathy and renal disease[4]. The discovery of the (pro)renin receptor (PRR), which binds both renin and its precursor, and the successful development of the first orally effective renin inhibitor has opened new avenues in the field of RAS and CVD. Renin inhibition, with the potential for augmented antagonism of RAS, could help to prevent the epidemic of CVD which continues unabated despite the use of ACE inhibitors and ARBs[5].

Figure 1
Figure 1 Schema of the renin-angiotensin system. ATR: Angiotensin II receptor; MAS: Mas proto-oncogene receptor; ACE: Angiotensin converting enzyme.

The first and the rate-limiting step in the RAS pathway is the conversion of angiotensinogen to Ang I by renin (Figure 1). Renin hydrolyzes the Leu10-Val11 bond of angiotensinogen, to generate the decapeptide Ang I

[Ang-(1-10)][6]. ACE present in the endothelium and tissues, as well as non-ACE pathways such as chymase, cathepsin G, and kallikrein-like enzymes, convert Ang I to the octapeptide Ang II. Ang II, acting through its receptors, type 1 (ATR1) and type 2 (ATR2), is responsible for the acute and the chronic effects of RAS. Ang II promotes renal and systemic arteriolar constriction and reabsorption of sodium in the proximal segments of the nephron, effects which could be beneficial in acute injury by preservation of intravascular volume, maintenance of blood pressure and repair of vascular injury[7]. However, chronic activation of ATR1 leads to abnormal gene expression and tissue remodeling, such as an increase in the synthesis of aldosterone by the adrenal zona glomerulosa, and increased expression of matrix proteins such as collagens I and III[8] and fibronectin[9,10]. In contrast, ATR2 stimulation provides cardiorenal protection through receptor-mediated vasodilatation, kinin-mediated anti-proliferative and pro-apoptotic effects in the heart and vasculature, and beneficial effects on sodium reabsorption by the proximal tubules of the kidney[11].

As shown in Figure 1, there are other active metabolites that are products of the RAS, of which, Ang-(1-7)[12,13] is the most important. Ang-(1-7) can be produced by the action of tissue endopeptidases especially neprilysin on Ang I[14-16], or from Ang II by the action of angiotensin converting enzyme 2 (ACE2). Ang-(1-7) opposes the endogenous actions of tissue Ang II, provides cardiorenal protection by binding to the Mas protooncogene receptor[17]. Apart from its anti-arrhythmogenic, antithrombotic and growth inhibitory effects, the most prominent effect of Ang-(1-7) is the inhibition of the Ang II-induced vasoconstriction[18-20]. Ang-(1-7) is subsequently metabolized by ACE and aminopeptidases to inactive fragments Ang-(1-5), Ang-(1-4), Ang-(2-7) and Ang-(3-7)[21]. Ang III [Ang-(2-8)] and Ang IV [Ang-(3-8)] are also produced by cleavage of Ang II. The functional role of Ang III and IV is relatively unclear, Ang III being a less potent stimulator than Ang II, and Ang IV playing a role in regulating local blood flow to the brain[22]. Ang-(1-12)[20], a relatively new addition to the family of RAS effectors, is produced directly from angiotensinogen by a non-renin enzyme. It contains the 12 amino acids from the N-terminus of angiotensinogen and can act as a precursor for the generation of Ang II by chymase[23].


Earlier research had shown that 2 proteins bind prorenin and renin, i.e. mannose 6-phosphate receptor (M6P-R)[24,25] and renin binding protein[26]. Renin bound to these receptors does not have any functional effect[27,28]. For example, after binding of prorenin to M6P-R, the M6P-R/prorenin complex is internalized and activated to mature renin by proteolysis, but this intracellular renin is degraded and does not affect intra- or extracellular Ang II generation. In contrast to these earlier studies, Nguyen et al[29,30] discovered that renin binding to surface receptors on cultured human mesangial cells induced a hypertrophic effect and an increase in the expression of plasminogen activator inhibitor-1. Six years after their initial report, Dr Nguyen’s group identified the specific receptor by expression cloning that eventually came to known as the (pro)renin receptor since it was found to bind both renin and prorenin[31].

Biology of the prorenin receptor

The PRR is a 35 kDa protein consisting of 2 fragments: an extracellular soluble N-terminal domain and a C-terminal domain. The N-terminal (28 kDa) domain of the PRR specifically binds to renin and prorenin (Figure 2). The C terminal domain of the receptor has a cytoplasmic and a transmembrane domain[31,32], and is homologous to a 8.9-kDa truncated protein termed M8-9 which was recently renamed ATP6ap2, and can associate with the vacuolar H(+)-ATPase, which plays an important role in acidification of urine[33,34]. The presence of the PRR has also been demonstrated in the glomerular mesangium[35], in the sub-endothelium of coronary and renal arteries, and in smooth muscle cells[36]. The highest concentration of mRNA for PRR is seen in the heart, brain, placenta, with lower levels reported in the kidney and liver[31].

Figure 2
Figure 2 Signal transduction mediated by the (pro)renin receptor. PRR: (Pro)renin receptor.

Traditionally, human prorenin was considered as the enzymatically inactive biosynthetic precursor of renin[37]. In addition to the juxtaglomerular cells of the kidneys (which also secrete renin) prorenin is secreted by reproductive organs, adrenal gland, eye and the submandibular gland[38]. Two pathways of activation of prorenin to renin have been described: proteolytic and non-proteolytic. The proteolytic conversion of prorenin to renin occurs by the cleavage of the 43-amino acid N-terminal prosegment in juxtaglomerular cells to produce the active metabolite renin, an aspartyl protease[39,40]. There are 2 forms in which the prorenin molecule exists: open and closed. It has been suggested that prorenin is a precursor renin with an amino acid chain (prosegment) that covers the cleft containing the active site and thus prevents access of angiotensinogen (Figure 2), which is considered the closed conformation and accounts for 98% of prorenin under physiological conditions. However, at acidic pH prorenin undergoes a conformational change to expose its active site[41]. Interestingly, irrespective of whether renin or prorenin is present in the open (active) conformation after binding to the PRR, they are capable of converting angiotensinogen to angiotensin I[31,42].

Based on the mechanism of non-proteolytic activation of prorenin to renin, Suzuki et al[43], formulated the theory of “gate and the handle”. They proposed that the prosegment, which was termed the “handle region”, folds into an active site cleft of prorenin to prevent catalytic conversion of angiotensinogen to Ang I (Figure 2). They also proposed that any synthetic protein that mimics the handle region, i.e. handle region peptides (HRP), can bind to the catalytically active site of prorenin and prevent its non proteolytic activation (decoy hypothesis). This theory was later validated, albeit with limited success. HRP infusion normalized an elevated renal Ang II level in diabetic rats[44]. Rat HRP infusion completely prevented the development of diabetic nephropathy in hemi-nephrectomized streptozocin-induced diabetic rats and also caused the regression of established diabetic nephropathy[45,46]. HRP was also demonstrated to reduce cardiac Ang II levels and cardiac fibrosis in stroke-prone spontaneously hypertensive rats without affecting blood pressure[47]. However, later studies showed that HRP failed to affect prorenin binding and prorenin-induced Ang I generation in vascular smooth muscle cells overexpressing the human PRR, even at relatively high concentration[48]. Chronic HRP infusion also did not ameliorate target organ damage in Goldblatt hypertensive rats[49]. Attempts to reproduce the effects of HRP in vivo were also unsuccessful[50].

The role of tissue activation of PRR independent of the plasma concentration has been investigated in recent years. The level of prorenin in the human plasma is approximately 10-fold higher than that of renin (0.5 pmol/L)[51]. The Kd value of PRR for prorenin and renin is 5 nmol/L and 20 nmol/L, respectively[52,53]. In spite of the high concentration of prorenin in human plasma, its level is not adequate enough to bind to PRR. Thus, significant prorenin binding to its receptor occurs only at tissue sites where it is produced locally, i.e. in kidneys, ovaries, testis, adrenal gland, and eye[39]. Similarly, the high renin concentration required to activate PRR may occur only in the kidneys.

Prorenin receptor signal transduction

The binding of the PRR by prorenin or renin triggers intracellular signaling and activates 3 main pathways (Figure 2). The most important of these, the extracellular signal-regulated kinase (ERK) 1/2 signaling pathway has been shown to be activated in mesangial cells[30], vascular smooth muscle cells[53], cardiomyocytes[54] and renal tubular epithelial cells[54,55] in an Ang II-independent manner. Signal transduction via the ERK pathway upregulates transforming growth factor β1 gene expression[56,57] as well as the genes coding for the plasminogen activator inhibitor-1[56], collagens, fibronectin and cyclooxygenase-2[58]. Ligand binding to PRR also activates the p38 mitogen-activated protein kinase (MAPK)-heat shock protein 27 cascade[59,60] and the promyelocytic zinc finger protein-phosphatidylinositol-3kinase-p85α pathway[61]. These varied signal transduction pathways are independent of Ang II generation and follow binding of both renin and prorenin to the PRR.

Other than signal transduction via the above-mentioned pathways, vacuolar H+-ATPase which has been co-localized with PRR has been shown to have a key role in urinary acidification[34]. The gene for the PRR/ATP6ap2 component of the vacuolar H+-ATPase is conserved across a wide range of vertebrate and invertebrate species and mutation of the ATP6ap2 gene in zebrafish leads to their death early during development[33]. Recently, cardiomyocyte specific ablation of Atp6ap2 has been shown to result in lethal heart failure[62].


Initial renin inhibitors were peptides, and hence had poor bioavailability, rapid rates of elimination and weak antihypertensive activity. Therefore, they never entered the clinical arena[63]. In 2003, by using a combination of molecular modeling and crystallographic analysis, Wood et al[64] designed a novel renin inhibitor, aliskiren [(2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy) phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanamide], which did not require the extended peptide-like backbone of earlier inhibitors[65,66]. The addition of various aromatic side chains dramatically increased its affinity for renin and increased its duration of action[65]. Aliskiren is highly soluble in water (350 mg/mL at pH 7.4), and has a molecular weight of 609.8 Da (551.8 Da as the free base)[64].

Pharmacokinetic properties

Aliskiren is rapidly absorbed through the oral route reaching a maximum plasma concentration within 1-3 h[67,68]. However, it has low bioavailability: 2.4% in rats, 16% in marmosets, and approximately 2.6% in humans[69]. The plasma half-life of aliskiren in rats, marmosets and humans is 23, 26 and 23-70 h respectively[65,67,70-73]. When administered once daily, the steady state concentration of aliskiren is reached in 7-8 d[67]. Food intake reduces Cmax by 85% and area under the curve by 71%[69]. Recently, concomitant administration of grapefruit, orange and apple juices (inhibitors of organic anion transporting polypeptide 2B1 influx transporter) with aliskiren have been shown to reduce the plasma aliskiren area under the curve by 61%, 62% and 63%, respectively[74,75]. Thus, aliskiren should be taken carefully with regard to meals and in a routine manner to avoid any variability[69]. Aliskiren is moderately bound to plasma proteins (47%-51%) in human plasma. However, the free plasma concentration of aliskiren is not affected by pathophysiological changes in protein concentration as occurs in chronic diseases. The volume of distribution of aliskiren is estimated as 135 L after a single 20 mg intravenous injection in healthy subjects indicating substantial extravascular distribution[76].

In humans, only 20% of aliskiren is metabolized. The major enzymes responsible for this appears to be cytochrome P450 (CYP) 3A4[69,77]. Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C19, 2D6, 2E1 and CYP3A)[66]. Age has a modest impact on aliskiren bioavailability in healthy volunteers[68]. However, in clinical trials, the safety and tolerability was similar in the 2 groups[67]. A pooled analysis of 7 clinical trials showed that the area under the curve and Cmax were slightly lower in the healthy male (24%) than in the healthy female (30%) population, which was thought to be due to a lower bodyweight in females (66.0 kg) as compared to males (78.5 kg)[69]. However, in clinical trials, there was no difference in blood pressure lowering efficacy, or safety and tolerability in women compared to men[78]. Similarly, race does not significantly influence the pharmacokinetics of aliskiren[67,69]. The dose of aliskiren does not need to be changed in the presence of hepatic and renal impairment though caution is advised in the presence of severe renal failure, particularly in those with sodium depletion[69].

No clinically significant pharmacokinetic drug-drug interaction was noted with commonly used antihypertensives, such as ramipril, valsartan, amlodipine, hydrochlorothiazide, atenolol[79,80], antihyperglycemic medications such as metformin and pioglitazone[69], lipid-lowering agents such as lovastatin and fenofibrate, the cardiac glycoside digoxin[81] or the antianginal drug isosorbide mononitrate. Co-administration of P-glycoprotein inhibitors like atorvastatin, ketoconazole or cyclosporine resulted in significant increases in aliskiren levels. Concomitant use of aliskiren with cyclosporine is not recommended.

Potential benefits of renin inhibition over traditional methods of RAS antagonism

An important reason for the suboptimal success of ACE inhibitors, ARB, aldosterone antagonists and their combination could be the phenomenon termed “ACE escape”. Even maximal doses of ACE inhibitors do not completely suppress the production of Ang II[82], since ACE-independent pathways such as chymase, cathepsin G and kallikrein-like enzymes also contribute to Ang II production. In humans these alternate pathways may be responsible for up to one-third of Ang II. The importance of these pathways becomes even more important at the level of end organs especially heart[83], kidney[84] and the vascular endothelium[85]. The other important rationale for ACE escape is a reactive rise (due to interruption of Ang II negative feedback) in plasma renin concentration (PRC) and more importantly plasma renin activity (PRA) (Table 1). An elevated PRA eventually leads to increased Ang II production, and is associated with an increased risk of major cardiovascular events, cardiovascular death, all-cause mortality and heart failure in high-risk patients with stable chronic vascular disease and/or diabetes[86-88].

Table 1 Effect of commonly used antihypertensives on effectors of the renin-angiotensin system.
PRCPRAAng IAng IIAng IIIAng IVAng-(1-7)
DiureticsNot knownNot known1/Not known
CCBNot knownNot knownNot known
β blockersNot knownNot known2/Not known

Renin inhibition, by inhibiting the first and rate limiting step in the RAS cascade, and by inhibiting the activity of elevated levels of renin, could lead to more complete blockade of the RAS than that obtained by the use of ACE inhibitors and ARBs. Although renin inhibition leads to higher levels of PRC than seen with ACE inhibition or ARBs, PRA is considerably reduced. The concept has been validated by multiple clinical trials. In a crossover study of 12 mildly sodium depleted normotensive healthy human volunteers, aliskiren decreased PRA and urinary aldosterone levels compared with valsartan[71]. Multiple studies have shown similar favorable comparisons with standard antihypertensives in sodium replete normotensive subjects as well as in mild to moderately hypertensive patients[89-93]. However, Sealey and Laragh have questioned the long term efficacy of this approach[94], postulating that the reactive increase in PRC might overcome the inhibitory effects of aliskiren, as evidenced by the fact that a few patients in clinical trials had a rise in blood pressure after administration of aliskiren. This issue was examined by Stanton et al[95], who performed a meta-analysis using data on 4877 patients enrolled in 8 randomized, double blind, placebo- and/or active-controlled trials. There were no significant differences in the frequency of increases in systolic (>10 mmHg, P = 0.30) or diastolic (> 5 mmHg, P = 0.65) pressure among those treated with aliskiren (3.9% and 3.1%, respectively), angiotensin receptor blockers (4.0% and 3.7%), ramipril (5.7% and 2.6%), or hydrochlorothiazide (4.4% and 2.7%). Increases in blood pressure were considerably more frequent in the placebo group (12.6% and 11.4%, P < 0.001). In contrast, Nussberger et al[96] have demonstrated that the greatest blood pressure lowering effect of aliskiren occurred in patients with high baseline PRA, while its effects were considerably less pronounced in those with low PRA.

Another potential benefit of aliskiren relates to its prolonged half-life (23-70 h). Andersen et al[97] performed a randomized controlled trial in which aliskiren and ramipril were administered for 6 mo followed by a controlled withdrawal of the medications. The change in the level of PRA, PRC and control of the blood pressure 2 wk after the discontinuation of each medication was assessed. Four wk after stopping aliskiren-based therapy, PRA remained 52% below pre-treatment baseline in contrast to the ramipril group in which PRA returned to baseline after 2 wk. In parallel with PRA, most of the blood pressure lowering effects of ramipril-based treatment disappeared 1 wk after stopping therapy. In contrast, median blood pressure values did not exceed 140/90 mmHg even at 4 wk after stoppage of aliskiren. The gradual return of BP towards baseline levels observed after stopping aliskiren-based therapy reflects the prolonged effects of aliskiren on PRA. In animal studies it has been demonstrated that aliskiren tends to substantially accumulate in the kidneys[98]. The accumulation and slow release of aliskiren from the kidneys after stopping treatment may explain the persistent effects of aliskiren on PRA beyond the half-life of the drug[99]. Prolonged suppression of PRA could be clinically beneficial especially in those patients whose compliance is inadequate.

Preclinical studies of aliskiren

Wood et al[100] were the first to demonstrate the benefit of aliskiren in lowering blood pressure in sodium depleted marmosets and spontaneously hypertensive rats. An important limitation for preclinical studies is the fact that renin is a species-specific enzyme. For example, the IC50 of the oral human renin inhibitor aliskiren for rat renin is 100-fold the value for human renin (0.6 nm). A double transgenic rat model overexpressing human renin and angiotensinogen genes has been used to study the effects of renin inhibition on end organ protection[101]. In this model, aliskiren (3 and 0.3 mg/kg per day administered subcutaneously) decreased blood pressure, albuminuria, and left ventricular hypertrophy, and improved survival[102]. These effects were found to be as effective as high dose valsartan (10 mg/kg per day) and more prominent than low dose valsartan (1 mg/kg per day). In another study utilizing the same model, aliskiren attenuated increases in myocardial oxidant stress and fibrosis, while the ARB irbesartan demonstrated greater reductions in blood pressure and myocardial oxidant stress[103]. Similarly, Whaley-Connell et al[104] demonstrated that aliskiren and irbesartan produced similar reductions in albuminuria and renal oxidant stress and RAS activation in this model. Aliskiren has recently been shown to provide protection against the development of doxorubicin-induced acute cardiomyopathy in rats[105]. Pretreatment with aliskiren significantly reduced the rise in malondialdehyde levels and attenuated doxorubicin-induced inhibition of glutathione activity in the myocardium. Aliskiren has also been shown to improve cardiac function and remodeling after myocardial infarction independent of blood pressure control[106], prevent the development of atherosclerosis in mice[107], and improve systemic insulin resistance[108] and pancreatic remodeling[109] in transgenic Ren2 rat which overexpress tissue renin, and ameliorate chlorhexidine digluconate-induced peritoneal fibrosis in rats[110].

The mechanisms of the putative beneficial effects of aliskiren on end organ protection are still a matter of debate. Not every tissue synthesizes renin locally, but depends on the extraction of renin from the blood[111,112]. It is possible that locally produced prorenin could generate Ang I. Also, as described before, the binding of renin or prorenin to their receptor also activates the MAPK/ERK-1/2 signaling pathway. The activation of the intracellular pathway is independent with no correlation with the production of the Ang II. So far, in vitro studies have failed to show any effects of aliskiren on blocking this signaling pathway, and aliskiren does not affect the binding of renin or prorenin to their receptor[54,113,114]. Hence, based on current evidence, it could be surmised that the beneficial effects of aliskiren are most likely due to the prevention of the production of Ang II both at the systemic and local tissue level.

Effect of aliskiren in clinical hypertension

Aliskiren is an effective medication for the treatment of hypertension[115]. Stanton et al[116] found that aliskiren reduced daytime ambulatory systolic pressure in a dose-dependent manner. In a pooled analysis of patients with mild to moderate hypertension, aliskiren 150 and 300 mg showed a mean reduction in systolic blood pressure of 8.7-13.0 mmHg and 14.1-15.8 mmHg respectively when compared with placebo (2.9-10.0 mmHg)[117]. The mean reduction in diastolic blood pressure was 3.3-8.6 mmHg, 7.8-10.3 mmHg and 10.3-12.3 mmHg with placebo, 150 mg aliskiren and 300 mg aliskiren, respectively. The antihypertensive effect of aliskiren has been shown to be comparable in men and women[77] and consistent across subgroups of age[77], metabolic syndrome[118,119] and obesity[77].

The long pharmacological half-life of aliskiren makes it an ideal medication for once daily use. In a study involving 672 patients, the antihypertensive effect was maintained throughout a 24-h dosing period by 3 different doses of aliskiren (150, 300 and 600 mg)[120]. The effect of a daily dose of aliskiren of 150 mg is comparable with irbesartan 150 mg/d[121]. There is a minimal effect below the dose of 75 mg and a plateau of the dose response curve is reached at 300 mg. There is little or no additional blood pressure reduction with a higher dose of 600 mg. Overall, the tolerability profile of aliskiren is similar to that of placebo. The only adverse effect seen with aliskiren is diarrhea (9.5% with 600 mg; 2.3% with 300 mg; 1.2% with placebo). The higher occurrence of diarrhea is related to the high-unabsorbed fraction of the medication (77.5%)[69].

The antihypertensive effect of aliskiren is comparable to that of standard antihypertensive medications including hydrochlorothiazide[90], ramipril[97,122], lisinopril[123], losartan[116], irbesartan[121], valsartan[124] and amlodipine[92]. Furthermore, the antihypertensive effect of aliskiren has been found to be additive when combined with these medications. In large clinical trials, the effect of the combinations of aliskiren 300 mg with hydrochlorothiazide 25 mg[90] and with valsartan 320 mg[124] has been shown to have a synergistic effect. As a result, the US Food and Drug Administration has approved the use of the respective combinations in patients who are either not adequately controlled with monotherapy or as initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals. Apart from being a blocker of the RAS, the additive effect of aliskiren in combination with hydrochlorothiazide, valsartan and amlodipine may also be explained by its ability to suppress elevated PRA caused by diuretics, ACE inhibitors, ARB and vasodilators (Table 1).

Effectiveness of aliskiren on end-organ disease

Urine protein excretion in diabetic nephropathy is a predictor of non-fatal and fatal cardiovascular outcomes[125,126]. It has been well demonstrated that patients with diabetic nephropathy have a high baseline serum prorenin level[127]. Interestingly, these patients have normal or suppressed PRA levels[128]. Prorenin has been proposed as a therapeutic target to slow the progression of diabetic nephropathy[129]. In a randomized double-blind study which enrolled 599 diabetic patients with concomitant hypertension and nephropathy on standard treatment, the addition of aliskiren significantly reduced the urine albumin to creatinine ratio without a significant reduction in blood pressure[130]. Also, aliskiren has proven to be a potent renal vasodilator with a pronounced natriuretic effect in normotensive individuals on a low sodium diet as compared to that induced by ACE inhibitors[131]. Another study demonstrated that aliskiren increased renal plasma flow and glomerular filtration rate in healthy subjects[132]. These studies suggest the renoprotective potential of aliskiren.

The Aliskiren in Left Ventricular Hypertrophy Trial was a non-inferiority trial in which 465 patients with hypertension, increased left ventricular wall thickness and body mass index > 25 kg/m2 were randomized to receive aliskiren 300 mg, losartan 100 mg, or their combination daily for 9 mo[133]. Additional agents with the exception of β-blockers and other RAS modulators were allowed for optimal blood pressure control. After 34 wk of treatment, a significant reduction in left ventricular mass index was achieved by the combination of aliskiren and losartan (-6.4%), by aliskiren alone (-5.4%) and by losartan (-4.7%). However, the differences across the 3 groups were not statistically significant.

The Aliskiren Observation of Heart Failure Treatment trial (ALOFT) examined the effect of aliskiren (150 mg/d) on N-terminal pro-brain natriuretic peptide levels in patients with heart failure and class II-IV New York Heart Association symptoms[134]. After 3 mo of treatment N-terminal pro-brain natriuretic peptide level was found to be reduced by 244 ± 2025 pg/mL with aliskiren (P = 0.0106) compared with an increase in the placebo group by 762 ± 6123 pg/mL. The urinary aldosterone concentration was also reduced by aliskiren. The addition of aliskiren to standard therapy was well tolerated with a statistically nonsignificant increase in the rate of hypotension and hyperkalemia. This study suggested that aliskiren could modulate neurohumoral activation in heart failure when added to standard therapy.

The results of the ASPIRE study (Aliskiren Study in Post Myocardial Infarction Patients to Reduce Remodeling)[135] were presented recently. This randomized controlled trial enrolled 820 patients who were within 1-6 wk of myocardial infarction and had a left ventricular ejection fraction of < 45% and an infarct size (segment length) of > 20%. All the patients were receiving standard therapy including antiplatelet agents, statins, β-blockers and ACE inhibitors or ARBs. Patients were randomized to placebo or aliskiren 300 mg/d to examine the effect on the primary endpoint of change in left ventricular end systolic volume at week 36. There was no statistically significant difference between the 2 groups (-3.5 ± 16.3 mL for placebo vs -4.4 ± 16.8 mL for aliskiren). There was no difference in end diastolic volume, ejection fraction or cardiovascular outcomes between the 2 groups. There was a higher incidence of renal dysfunction, hypotension and hyperkalemia in the aliskiren group compared with the placebo, as well as a significant drop in blood pressure in the treatment group. This study raised some concerns about the use of aliskiren in post-myocardial infarction patients with systolic heart failure.

The recently reported Aliskiren and Valsartan to Reduce NT-proB-type natriuretic peptide via Renin-Angiotensin-Aldosterone-System Blockade (AVANT GARDE)-TIMI 43 Trial[136] examined the hypothesis that early inhibition of the RAS in patients with normal ventricular systolic function but with elevated natriuretic peptides following an acute coronary syndrome would reduce ventricular stress as measured by N-terminal pro-brain natriuretic peptide levels. The effect of aliskiren, valsartan, and their combination was similar to placebo, while adverse events were more frequent in the treatment arm compared to placebo.

As described above, short- to intermediate-term studies have yielded mixed results on the effect of aliskiren on cardiovascular and other end organ protection. The ASPIRE HIGHER clinical trials program, a comprehensive group of 14 clinical trials, includes 4 large ongoing morbidity and mortality trials which may provide more conclusive answers on the role of direct renin inhibition in cardiovascular protection. The Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Disease Endpoints Trial (ALTITUDE) is evaluating the effect of aliskiren on cardiorenal end points in patients with type 2 diabetes and either renal or cardiovascular pathology. The Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE) Trial is examining the effect of aliskiren, enalapril and their combination in chronic systolic heart failure, while the Aliskiren Trial On Acute Heart Failure Outcomes (ASTRONAUT) Trial is evaluating the effect of aliskiren on outcomes in acute heart failure. The Aliskiren in Prevention of Later Life Outcomes (APOLLO) Trial will assess the effect of aliskiren on cardiovascular, functional and cognitive outcomes in an elderly population.


Renin inhibitors offer a novel method of RAS inhibition, alone and in combination with other antagonists of the RAS. Even though they are effective antihypertensive agents, the role of direct renin inhibition in cardiovascular protection is still a matter of debate. Although there are theoretical advantages of renin inhibitors in providing a greater degree of RAS suppression, the effect of elevated prorenin and renin levels through signal transduction via the PRR adds uncertainty to the overall effect of direct renin inhibition at the tissue level. Ongoing basic research and large randomized trials will shed more light on the role of this exciting new class of drug.


Peer reviewer: Ismail Laher, Professor, Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, 2176 Health Sciences Mall, Vancouver, V6T 1Z3, Canada

S- Editor Cheng JX L- Editor Cant MR E- Editor Zheng XM

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