Current Hypertension Reviews (v.8, #1)

Renin-angiotensin system (RAS) has a major role in hypertension, diabetes, obesity, and diseases that are caused by these conditions. Inhibition of the RAS has been clinically proven beneficial in hypertension, atherosclerosis, coronary artery disease, heart failure, stroke, nephropathy, and neuropathy, among many others. The dominant concept of the RAS defines this as a circulating system consisting of renin, angiotensinogen, and angiotensin converting enzyme (ACE), which produces a potent peptide hormone angiotensin (Ang) II. Most of the pathological effects of the RAS are brought about by binding of Ang II to two specific angiotensin receptors, type 1 (AT1) and type 2 (AT2). Clinically, two major classes of drugs, ACE inhibitors and angiotensin receptor blockers (ARBs), which prevent generation of Ang II or binding to receptors, are in use. A new drug, which is a renin inhibitor, has recently been approved for clinical use. ACE inhibitors and ARBs have been used extensively in the clinic and proven beneficial. However, there is a growing realization that a full benefit of blocking RAS has not been achieved using these two classes of drugs. The latter is likely due to the reactive activation of the RAS following treatment with these drugs. A combination therapy of ACE inhibitors and ARBs has not provided better outcome. Similar concerns regarding reactive rise in renin levels have been opined about the renin inhibitor. A need for alternative drugs and strategies to inhibit the RAS has been felt for some time. As is apparent, all three classes of drugs are based on the classical concept of the RAS.....

The renin-angiorensin system (RAS) is an important regulator of vascular volume and cardiovascular structure. Inhibitors of the RAS appear to provide benefits in addition to those associated with blood pressure lowering in disorders such as diabetic nephropathy, and congestive heart failure. Early successes led to the speculation that improved blockade of the RAS could produce further benefits. Although improved blockade can be achieved by combining angiotensin converting enzyme inhibitors and angiotensin receptor blockers, there is no convincing evidence that this strategy can substantially improve the outcome of hypertension, congestive heart failure, or diabetes over that currently achievable. There is even evidence to suggest that too complete a blockade of the RAS could be detrimental, likely as the result of diminished cardiovascular homeostasis. Collectively, these observations suggested that the benefits of strategies directed at the RAS may have achieved their maximal potential to produce benefit. However, it has become increasingly clear that the renin-angiotensin system is substantially more complex than previously appreciated. Effector proteins other than angiotensin II have been identified and tissue/cellular RASs have been defined. As a result, rather than closing the book on RAS- based therapeutics, current research may actually be opening an entirely new chapter.

Renin-angiotensin system (RAS) is known to be a regulator of blood pressure, volume homeostasis, and cardiovascular growth and remodeling, but is still incompletely understood. Tissue RAS plays important roles in development of target-organ damages in pathological states such as hypertension and diabetes. The pathophysiological roles of (pro)renin receptor [(P)RR] have been growing concern. (P)RR binds renin and prorenin, with two important consequences, nonproteolytic activation of prorenin and the intracellular signalings. In this article, we attempt to elucidate the possible pathophysiological roles of the (P)RR and the therapeutic potential in primary hypertension, through reviewing studies on animal models of hypertension, transgenic rats overexpressing (P)RR and genetic analysis in humans.

Chymase, a serine protease found in mast cell granules, is released into the interstitium following injury or inflammation. Chymase is the primary ACE-independent pathway of angiotensin II formation, and also functions to activate TGF-beta and other promoters of extracellular matrix degradation, thereby playing a role in tissue remodeling. In the diseased kidney, chymase-containing mast cells markedly increase and their density correlates with tubulointerstitial fibrosis severity. Studies in humans support the pathologic role of chymase in diabetic nephropathy, while animal studies form the basis for the importance of increased chymase-dependent angiotensin II formation in progressive hypertensive, diabetic and inflammatory nephropathies. Moreover, humans with kidney disease express chymase in diseased blood vessels in concordance with significantly elevated plasma chymase levels. Conversely, specific chymase inhibitors attenuate angiotensin II production and renal fibrosis in animal models, suggesting their potential therapeutic benefit in human nephropathy, where chymase-containing mast cells accumulate and contribute to progressive disease.

Mas Receptor Agonists as Novel Antihypertensive Agents by Silvia Quintao Savergnini (24-34).
It is well known that the renin-angiotensin system (RAS) plays a pivotal role in the control of the cardiovascular and renal systems and in the pathogenesis of cardiovascular and renal diseases. The classical concept of the RAS has been changed in the recent years by the inclusion of novels components. Among the novel components of the RAS, Angiotensin(Ang)-(1-7), its major forming enzyme angiotensin-converting enzyme (ACE) 2 and its receptor, the G protein-coupled receptor Mas, have been the subject of many recent studies aimed to clarify the role of this novel axis of the RAS. This axis appears to act as a counter-regulatory mechanism for the classical axis represented by ACE/Ang II/AT1 receptor in several conditions, including hypertension and others cardiovascular diseases. In this review we will focus on the potential use of Mas agonists as anti-hypertensive drugs.

Discovery of angiotensin converting enzyme (ACE)-2 provided a strong impetus for the development of novel therapeutic tools for the treatment of cardiovascular diseases (CVDs). Angiotensin (Ang)-(1-7), the product of ACE2, via activation of Mas receptor elicits cardiovascular protective effects to a large extent by counter-regulating ACE/Ang- II/AT1-receptor axis of renin angiotensin system (RAS). Bone marrow (BM)-derived progenitor cells play an important role in cardiovascular homeostasis. Angiogenic precursor cells (APCs) have received tremendous attention in the recent years for their therapeutic application for treatment of CVDs, where cardiovascular tissue regeneration is the desired outcome. Autologous cell therapy is a better treatment option for patients with cardiovascular complications. However, circulating APCs from these patients are dysfunctional limiting their therapeutic utility. Thus ex vivo modification to restore their regenerative potential is essential to improve outcomes of autologous cell therapies in CVD. Members of both pathological and protective axes of RAS have been identified in one or more types of BM-derived cells. Modulation of the function of APCs by Ang-II or Ang-(1-7) has now been implicated in the pathology and protection of cardiovascular systems, respectively. Thus, novel functions of RAS in the cardiovascular regenerative physiology and pharmacology are being unraveled. Accumulating evidence points to the ACE2/Ang-(1-7)/Mas axis as a promising target for the treatment of CVDs. The major focus of this review is to highlight the protective role of ACE2/Ang-(1-7)/Mas pathway in the reparative function of BM-derived cells for cardiovascular repair and regeneration.

In the classical view, the hormone angiotensin II (Ang II) mediates its action via two major receptors, namely the Ang II type-1 receptor (AT1R) and the type-2 receptor (AT2R). Several recent reviews implicate the renin-angiotensin system (RAS) in various aspects of adipose tissue physiology and dysfunction. Research on AT2R has long been hampered by at least three potential challenges, (i) the low expression level of the AT2R in the adult, (ii) the atypical signaling pathways of AT2R and (iii) the absence of appropriate selective ligands. Indeed, apart a few exceptions, the role of the AT2R was in fact revealed by the results of simultaneous treatment with Ang II and AT1R blockers or in AT2Rdeficient mice. The first aim of this review is to summarize current paradigms concerning the role of the AT2R in adipocyte differentiation and in metabolic disorders related to insulin resistance and type 2 diabetes. Secondly, we will highlight the potential utility of selective AT2R agonists in clarifying potential roles of the AT2R in adipocyte physiology. We summarized our findings using a selective and high affinity nonpeptide ligand of the AT2R and demonstrate that AT2R is involved in adipocyte differentiation and may improve insulin sensitivity in a model of insulin resistance, in addition to increase vasodilation and reduce inflammation in adipose tissue. Thus the recent development of orally active, selective AT2R agonists should facilitate efforts to elucidate the distinct roles of the AT2R in physiology, including adipocyte physiology.

Many conventional GPCRs such as those associated with apelin, endothelin, prostaglandin E2, and angiotensin have also been localized to the intracellular space, principally the nucleus. These observations have involved a broad range of tissues, isolated primary cells, and cell lines and a variety of techniques including confocal microscopy, immunohistochemistry, immunocytochemistry, and western blotting. Some receptors are transported to nucleus as holoreceptors while other receptors have been shown to be cleaved with only a portion of the receptor trafficking to nucleus. Several studies from many different laboratories indicate that, depending on the cell type, the angiotensin II type 1 receptor can exist in nuclear membrane or nucleosol and that nuclear accumulation can be induced by ligand-treatment. Moreover, a population of the angiotensin receptor is cleaved in response to angiotensin II and the cytoplasmic carboxyterminal fragment trafficks to nucleus and is a potent apoptotic reagent. In this review, we discuss AT1R cleavage in light of several other receptor cleavage events which similarly produce apoptotic fragments; functionally active intracellular cleavage fragments represent novel targets for drug development.

Novel Treatments in Diabetic Nephropathy by Usha Panchapakesan (71-78).
Although there have been major advances in the understanding of the molecular mechanisms that contribute to the development of diabetic nephropathy, targeted therapy that reduces the socioeconomic and personal burden of this disease is somewhat lacking. The incidence of diabetes and associated nephropathy is increasing with the main cause of mortality being related to cardiovascular causes. Novel therapies which are both “cardio-renal” protective seem the logical way forward. In this review we discuss the therapies that target the traditional renin angiotensin aldosterone pathway and highlight the need for newer pharmacological strategies that also offer cardiac and renal protection. Although not discussed at length in this review, the need for primary prevention by modifying lifestyle factors cannot be underestimated.