Discovery Of Angiotensin Research Articles

Transgenic angiotensin-converting enzyme 2 overexpression in the rat vasculature protects kidneys from ageing-induced injury

Chronic kidney disease is one of the leading causes of morbidity and mortality especially among the aged population. A decline in kidney function with ageing comparable to ageing-related processes in human kidneys has also been described in Sprague-Dawley (SD) rats. The renin-angiotensin-system (RAS) plays a pivotal role in the pathophysiology of cardiovascular and kidney disease and is a successful therapeutic target. The discovery of angiotensin-(1-7) (Ang(1-7)), mainly produced by angiotensin-converting enzyme 2 (ACE2), and its receptor MAS offered a new view on the RAS. This ACE2/Ang(1-7)/MAS axis counteracts most deleterious actions of the RAS in the kidney. In order to evaluate if activation of this axis has a protective effect in ageing-induced kidney disease we generated a transgenic rat model (TGR(SM22hACE2)) overexpressing human ACE2 in vascular smooth muscle cells. These animals showed a specific transgene expression pattern and increased ACE2 activity in the kidney. Telemetric recording of cardiovascular parameters and evaluation of kidney function by histology and urine analysis revealed no alterations in blood pressure regulation and basal kidney function in young transgenic rats when compared to young SD rats. However, with ageing, SD rats developed a decline in kidney function characterized by severe albuminuria which was significantly less pronounced in TGR(SM22hACE2) rats. Concomitantly, we detected lower mRNA expression levels of kidney damage markers in aged transgenic animals. Thus, our results indicate that vascular ACE2-overexpression protects the kidney against ageing-induced decline in kidney function, supporting the kidney-protective role of the ACE2/Ang(1-7)/MAS axis.

The renin-angiotensin system: going beyond the classical paradigms

Thirty years ago, a novel axis of the renin-angiotensin system (RAS) was unveiled by the discovery of angiotensin-(1−7) [ANG-(1−7)] generation in vivo. Later, angiotensin-converting enzyme 2 (ACE2) was shown to be the main mediator of this reaction, and Mas was found to be the receptor for the heptapeptide. The functional analysis of this novel axis of the RAS that followed its discovery revealed numerous protective actions in particular for cardiovascular diseases. In parallel, similar protective actions were also described for one of the two receptors of ANG II, the ANG II type 2 receptor (AT2R), in contrast to the other, the ANG II type 1 receptor (AT1R), which mediates deleterious actions of this peptide, e.g., in the setting of cardiovascular disease. Very recently, another branch of the RAS was discovered, based on angiotensin peptides in which the amino-terminal aspartate was replaced by alanine, the alatensins. Ala-ANG-(1−7) or alamandine was shown to interact with Mas-related G protein-coupled receptor D, and the first functional data indicated that this peptide also exerts protective effects in the cardiovascular system. This review summarizes the presentations given at the International Union of Physiological Sciences Congress in Rio de Janeiro, Brazil, in 2017, during the symposium entitled “The Renin-Angiotensin System: Going Beyond the Classical Paradigms,” in which the signaling and physiological actions of ANG-(1−7), ACE2, AT2R, and alatensins were reported (with a focus on noncentral nervous system-related tissues) and the therapeutic opportunities based on these findings were discussed.

The dual blockade of the renin-angiotensin system in Internal Medicine: after ONTARGET trial

BACKGROUND In the increasing progress of scientific knowledge, every new discovery is a basis for new problems. In fact, after the success of Angiotensin-Converting Enzyme (ACE)-inhibitors in different cardiovascular diseases, the evidence of the “escape” of ACE and the discovery of Angiotensin- Receptor Blockers (ARBs) became the basis for a new question: is a dual blockade of the Renin-Angiotensin System (RAS) correct? DISCUSSION The different trials carried out (also the latest ONTARGET) didn’t give reliable answers, because differences were found both in the various diseases (hypertension, heart failure, coronary disease, nephropathy, diabetic or not), and between the single drugs of the class. We can say that this combination treatment didn’t show reliable clinical efficacy yet, except in heart failure and in some subgroups of hypertensive patients, checking carefully serum electrolytes and renal function. But even though we haven’t got certain outcomes, the research goes on quickly and some other sites of modulation of RAS were identified, from its first phases (aliskiren as prototype of direct renin inhibitors).

A cornerstone in the history of hypertension: the seventieth anniversary of the discovery of angiotensin

In 1939, two independent teams, in Buenos Aires and Indianapolis, identified the polypeptide angiotensin. In 1934, Goldblatt et al. demonstrated that partial occlusion of the renal arteries produces hypertension in dogs, and Houssay in 1936 predicted the presence of a humoral mechanism and, with Fasciolo, demonstrated that the ischemic kidneys released a pressor substance that increased the recipient's blood pressure. Later on, Taquini proved that the rise in blood pressure that follows the re-establishment of circulation in kidneys was also produced by a plasmatic substance from the venous blood of acute ischemic kidneys and it was called 'hypertensin'. Then, they proved that it was the result of an enzymatic reaction in which renin was the enzyme and plasma the substrate. At the same time, in 1939, Page et al. postulated that renin activated by plasma becomes vasoactive and the substance was called 'angiotonin'. Page's group began in 1937, with the purification of renin, studying its renal hemodynamic effects. Later on, Page et al. acknowledged in 1943 the enzymatic nature of the system and renamed their so-called renin-activator as renin substrate. Both groups fused the two original names into 'angiotensin' during a meeting at Michigan in 1958, making the 'adventure of the discovery of angiotensin' a reality.

Angiotensin-Converting Enzyme 2

See related article, pages 729–736 There is a “new kid on the block” in the control of the renin-angiotensin system (RAS). The discovery of angiotensin (Ang)-converting enzyme (ACE)2, a catabolic enzyme, that cleaves the octapeptide, Ang II into a septapeptide, Ang-(1-7),1,2 has opened up new vistas in the way we think about the regulation and biological effects of Ang II. ACE 2 was originally discovered in yeast3 as a gene product that codes for a protein that is a homolog of the more widely known protease ACE. ACE2 cleaves the C-terminal amino acid from Ang II and other peptides. For many years, the work of Ferrario and Chappel4 provided evidence that Ang-(1-7) operated in the central nervous system, as well as in the peripheral circulation to produce effects that were, in general, opposite to that of Ang II. Recently, the discovery that Ang-(1-7) binds to a specific membrane receptor, the mas receptor,5–7 suggests that this metabolite may play a regulatory role in cell signaling and organ function. Clearly, the balance between the classic ACE and ACE2 will determine the physiological effect of activation of the RAS. Furthermore, the potential for therapeutic targeting of ACE2 and its role in the …

A comparison of the properties and enzymatic activities of three angiotensin processing enzymes: Angiotensin converting enzyme, prolyl endopeptidase and neutral endopeptidase 24.11

The discovery of angiotensin-(1–7) [Ang-(1–7)] as a bioactive Ang II fragment of the renin-angiotensin system (RAS) alters the current understanding of the enzymatic components that comprise the RAS cascade. Two neutral endopeptidases, prolyl endopeptidase (E.C. 3.4.21.26) and neutral endopeptidase 24.11 (E.C. 3.424.11), are capable of forming Ang-(1–7) from Ang I and habe been implicated in the in vivo processing of Ang I. This makes them putative Ang processing enzymes and part of the RAS cascade. This review summarizes the physical characteristics and distribution of angiotensin converting enzyme (E.C. 3.4.15.1), a known Ang I processing enzyme, and compares its features to what is known of prolyl endopeptidase and neutral endopeptidase 24.11.