1. Introduction

Cardiovascular diseases (CVD) account approximately one third of the total deaths, totaling ≈17 million annually worldwide [78]. Hypertension is considered one of the key risk factors for the development of CVD such as coronary heart diseases, peripheral artery disease and stroke, and kidney disease. Hypertension is often termed as "silent killer" affecting 1 billion people worldwide and causes up to 9 million deaths every year. In addition to health burden, treatment and prevention of hypertension are also associated with substantial socioeconomic consequences. A range of synthetic drugs, such as direct vasodilators, diuretics, adrenergic inhibitors, and angiotensin converting enzyme inhibitors, are commonly used for the treatment of hypertension [50]. The estimated costs for treating hypertension and related diseases were \$156 billion in the USA in 2011 and nearly €110 billion in Europe in 2006. Healthy lifestyle choices and early treatment for individuals with mild hypertension are of high importance for reducing the global healthcare costs [50].

In addition to nutritive value of food proteins, they can have various biological activities either intact or after released during processing or digestion. The active peptide fragments, bioactive peptides, can exert beneficial effects on human health in addition to nutritional value. These fragments can be released from various food proteins by gastrointestinal digestion or food processing. According to the Biopep and BioPD (bioactive peptide database) databases, more than 1200 different bioactive peptides have been recorded. These peptides have 2–20 amino acids and molecular masses of less than 6000 Da. Their bioactivity is mainly determined by their composition and amino acid sequence [17, 56, 64]. Especially, peptides with antihypertensive activity have received the significant attention due to the persistence of hypertension and its associated complications. Inhibition of angiotensin I converting enzyme (ACE) has been the main target of these peptides. ACE plays crucial role through renin-angiotensin system (RAS) in the regulation of blood pressure and electrolyte balance in human body. At present, the correlation between in vitro and in vivo antihypertensive activities appears to be weak [18, 23]. To develop effective antihypertensive peptides, it is important to understand the complex pathophysiology of hypertension and the potential targets where these bioactive peptides may exert their specific actions. This review provides an overview of food-derived peptides that may mediate the antihypertensive activities through inhibiting renin, one of the key enzymes in RAS.

## 2. Renin-angiotensin-aldosterone system

In cascade system of blood pressure regulation, the renin-angiotensin-aldosterone system (RAAS) plays a key role. The importance of RAAS in diseases such as hypertension, congestive heart failure, and chronic renal failure has been recognized; moreover, the inhibition of RAAS is an effective way to intervene with the pathogenesis of these disorders [11, 43]. Secretion of renin (EC 3.4.23.15) is the first step in RAAS pathway and, importantly, also the rate-limiting step of the RAAS by converting angiotensinogen (Ang) into inactive decapeptide angiotensin I (Ang I), which is converted at the endothelial surface of blood vessels by the enzyme ACE into angiotensin II (Ang II), the primary effector molecule of the RAAS. Therefore, physiological total renin activity, measured as plasma renin activity, can reliably indicate the risk of hypertension, and the inhibition of renin activity by natural products can be explored for the management of hypertension. Inhibition of renin could provide a more effective treatment for hypertension as it prevents the formation of Ang-I, which can be converted to angiotensin II (Ang-II), the vasoconstrictor compound, independent of ACE, by the enzyme chymase. In addition, unlike ACE which acts on a number of substrates, angiotensinogen is the only known substrate of renin. ACE inhibitors and AT1 receptor blockers (ARBs) are proven to be effective therapeutic agents in the treatment of CVD. However, both ACE inhibitors and ARBs lead to a substantial compensatory rise of circulating active renin and Ang peptides that may eventually limit their therapeutic potential [24, 67]. Moreover, the increased Ang I can be converted to Ang II by nonACE pathways, mediated by chymase and chymotrypsin-like enzyme. In addition to the side effects of ACE inhibitors, such as cough and angioedema, a meta-analysis of randomized controlled trials in 2010 suggested that ARBs are associated with a modestly increased risk of new cancer diagnosis, although conclusions about the exact risk of cancer associated with each particular drug have not been drawn [65]. Therefore, direct renin inhibition may be an alternative pharmacological approach to RAS inhibition.

1. Introduction

242 Renin-Angiotensin System - Past, Present and Future

key enzymes in RAS.

tance for reducing the global healthcare costs [50].

2. Renin-angiotensin-aldosterone system

Cardiovascular diseases (CVD) account approximately one third of the total deaths, totaling ≈17 million annually worldwide [78]. Hypertension is considered one of the key risk factors for the development of CVD such as coronary heart diseases, peripheral artery disease and stroke, and kidney disease. Hypertension is often termed as "silent killer" affecting 1 billion people worldwide and causes up to 9 million deaths every year. In addition to health burden, treatment and prevention of hypertension are also associated with substantial socioeconomic consequences. A range of synthetic drugs, such as direct vasodilators, diuretics, adrenergic inhibitors, and angiotensin converting enzyme inhibitors, are commonly used for the treatment of hypertension [50]. The estimated costs for treating hypertension and related diseases were \$156 billion in the USA in 2011 and nearly €110 billion in Europe in 2006. Healthy lifestyle choices and early treatment for individuals with mild hypertension are of high impor-

In addition to nutritive value of food proteins, they can have various biological activities either intact or after released during processing or digestion. The active peptide fragments, bioactive peptides, can exert beneficial effects on human health in addition to nutritional value. These fragments can be released from various food proteins by gastrointestinal digestion or food processing. According to the Biopep and BioPD (bioactive peptide database) databases, more than 1200 different bioactive peptides have been recorded. These peptides have 2–20 amino acids and molecular masses of less than 6000 Da. Their bioactivity is mainly determined by their composition and amino acid sequence [17, 56, 64]. Especially, peptides with antihypertensive activity have received the significant attention due to the persistence of hypertension and its associated complications. Inhibition of angiotensin I converting enzyme (ACE) has been the main target of these peptides. ACE plays crucial role through renin-angiotensin system (RAS) in the regulation of blood pressure and electrolyte balance in human body. At present, the correlation between in vitro and in vivo antihypertensive activities appears to be weak [18, 23]. To develop effective antihypertensive peptides, it is important to understand the complex pathophysiology of hypertension and the potential targets where these bioactive peptides may exert their specific actions. This review provides an overview of food-derived peptides that may mediate the antihypertensive activities through inhibiting renin, one of the

In cascade system of blood pressure regulation, the renin-angiotensin-aldosterone system (RAAS) plays a key role. The importance of RAAS in diseases such as hypertension, congestive heart failure, and chronic renal failure has been recognized; moreover, the inhibition of RAAS is an effective way to intervene with the pathogenesis of these disorders [11, 43]. Secretion of renin (EC 3.4.23.15) is the first step in RAAS pathway and, importantly, also the rate-limiting step of the RAAS by converting angiotensinogen (Ang) into inactive decapeptide angiotensin I (Ang I), which is converted at the endothelial surface of blood vessels by the enzyme ACE into angiotensin II (Ang II), the primary effector molecule of the RAAS. Therefore, physiological The first-generation renin inhibitors were peptide analogs prosegment of renin or substrate analogs of the amino-terminal sequence of angiotensinogen containing the renin cleavage site and were synthesized already more than 30 years ago. The second generation inhibitors were peptidomimetic agents that are dipeptide inhibitors of the active site. However, the clinical use of these renin inhibitors is limited due to poor metabolic stability and oral bioavailability, short duration of action, weak antihypertensive activity, and high cost of synthesis [61, 66]. Pepstatin, a statine-containing hexapeptide, is the first reported renin inhibitor, but the inhibitory activity of pepstatin was remarkably lower against renin than against pepsin [20]. An endogenously expressed renin-binding protein (RnBP) has been reported to inhibit renin activity [68] based on the selective binding mediated by a leucine zipper (f195–216) in RnBP [33]. The primary RnBP sequence in the renin-binding region is a valuable information for designing potent renin-inhibiting peptides that may be identified and released from food proteins using bioinformatic tools. Aliskiren is the only commercial clinically proven synthetic renin inhibitor for managing hypertension; it has been approved for use in Europe and the United States from 2007 [34]. It has been found to be a more effective antihypertensive agent than ACE inhibitors [74], but recent clinical evidence suggests that Aliskiren may be harmful to patients with type 2 diabetes who are at risk of developing cardiovascular and renal diseases [54].
