Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury, is a devastating clinical syndrome with a high mortality rate (30-60%) (refs 1-3). Predisposing factors for ARDS are diverse and include sepsis, aspiration, pneumonias and infections with the severe acute respiratory syndrome (SARS) coronavirus. At present, there are no effective drugs for improving the clinical outcome of ARDS. Angiotensin-converting enzyme (ACE) and ACE2 are homologues with different key functions in the renin-angiotensin system. ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 inactivates angiotensin II and is a negative regulator of the system. ACE2 has also recently been identified as a potential SARS virus receptor and is expressed in lungs. Here we report that ACE2 and the angiotensin II type 2 receptor (AT2) protect mice from severe acute lung injury induced by acid aspiration or sepsis. However, other components of the renin-angiotensin system, including ACE, angiotensin II and the angiotensin II type 1a receptor (AT1a), promote disease pathogenesis, induce lung oedemas and impair lung function. We show that mice deficient for Ace show markedly improved disease, and also that recombinant ACE2 can protect mice from severe acute lung injury. Our data identify a critical function for ACE2 in acute lung injury, pointing to a possible therapy for a syndrome affecting millions of people worldwide every year.

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Angiotensin-converting enzyme 2 protects from severe acute lung failure

The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.

https://pharmrev.aspetjournals.org/content/pharmrev/52/3/415.full.pdf

International Union of Pharmacology. XXIII. The Angiotensin II Receptors

Cardiovascular diseases are predicted to be the most common cause of death worldwide by 2020. Here we show that angiotensin-converting enzyme 2 (ace2) maps to a defined quantitative trait locus (QTL) on the X chromosome in three different rat models of hypertension. In all hypertensive rat strains, ACE2 messenger RNA and protein expression were markedly reduced, suggesting that ace2 is a candidate gene for this QTL. Targeted disruption of ACE2 in mice results in a severe cardiac contractility defect, increased angiotensin II levels, and upregulation of hypoxia-induced genes in the heart. Genetic ablation of ACE on an ACE2 mutant background completely rescues the cardiac phenotype. But disruption of ACER, a Drosophila ACE2 homologue, results in a severe defect of heart morphogenesis. These genetic data for ACE2 show that it is an essential regulator of heart function in vivo.

Angiotensin-converting enzyme 2 is an essential regulator of heart function

A growing body of evidence supports the notion that angiotensin II (Ang II), the central product of the renin-angiotensin system, may play a central role not only in the etiology of hypertension but also in the pathophysiology of cardiovascular and renal diseases in humans. In this review, we focus on the role of Ang II in cardiovascular and renal diseases at the molecular and cellular levels and discuss up-to-date evidence concerning the in vitro and in vivo actions of Ang II and the pharmacological effects of angiotensin receptor antagonists in comparison with angiotensin-converting enzyme inhibitors. Ang II, via AT(1) receptor, directly causes cellular phenotypic changes and cell growth, regulates the gene expression of various bioactive substances (vasoactive hormones, growth factors, extracellular matrix components, cytokines, etc.), and activates multiple intracellular signaling cascades (mitogen-activated protein kinase cascades, tyrosine kinases, various transcription factors, etc.) in cardiac myocytes and fibroblasts, vascular endothelial and smooth muscle cells, and renal mesangial cells. These actions are supposed to participate in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, atherosclerosis, and glomerulosclerosis. Furthermore, in vivo recent evidence suggest that the activation of mitogen-activated protein kinases and activator protein-1 by Ang II may play the key role in cardiovascular and renal diseases. However, there are still unresolved questions and controversies on the mechanism of Ang II-mediated cardiovascular and renal diseases.

Molecular and Cellular Mechanisms of Angiotensin II-Mediated Cardiovascular and Renal Diseases

There are two major angiotensin II receptor isoforms, AT1 and AT2. AT1 mediates the well-known pressor and mitogenic effects of angiotensin II, but the signalling mechanism and physiological role of AT2 has not been established. Its abundant expression in fetal tissues and certain brain nuclei suggest possible roles in growth, development and neuronal functions. Here we report the unexpected finding that the targeted disruption of the mouse AT2 gene resulted in a significant increase in blood pressure and increased sensitivity to the pressor action of angiotensin II. Thus AT2 mediates a depressor effect and antagonizes the AT1-mediated pressor action of angiotensin II. In addition, disruption of the AT2 gene attenuated exploratory behaviour and lowered body temperature. Our results show that angiotensin II activates AT1 and AT2, which have mutually counteracting haemodynamic effects, and that AT2 regulates central nervous system functions, including behaviour.

Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor

Angiotensinogen-deficient mice with hypotension.

Angiotensin II Type 1a Receptor-deficient Mice with Hypotension and Hyperreninemia

Chimeric renin-angiotensin system demonstrates sustained increase in blood pressure of transgenic mice carrying both human renin and human angiotensinogen genes

Maternal hypertension is a common complication of pregnancy and its pathophysiology is poorly understood This phenomenon was studied in an animal model by mating transgenic mice expressing components of the human renin-angiotensin system When transgenic females expressing angiotensinogen were mated with transgenic males expressing renin, the pregnant females displayed a transient elevation of blood pressure in late pregnancy, due to secretion of placental human renin into the maternal circulation Blood pressure returned to normal levels after delivery of the pups Histopathologic examination revealed uniform enlargement of glomeruli associated with an increase in urinary protein excretion, myocardial hypertrophy, and necrosis and edema in the placenta These mice may provide molecular insights into pregnancy-associated hypertension in humans

https://science.sciencemag.org/content/sci/274/5289/995.full.pdf

Hypertension Induced in Pregnant Mice by Placental Renin and Maternal Angiotensinogen

The renin-angiotensin system (RAS) is the most important regulator of electrolyte homeostasis and blood pressure. Our recently generated transgenic mice carrying either the human renin (hREN) or human angiotensinogen (hANG) genes did not develop hypertension but dual gene strains obtained by cross-mating separate lines of mice exhibited a chronically sustained increase in blood pressure, suggesting the presence of species-specific reactivity between renin and angiotensinogen. In order to examine this specificity, the present study was designed to perform a strictly comparative study on hydrolysis of hANG by hREN and mouse submandibular renin (mREN)in vitro by using pure proteins. The recombinant hANG (rhANG) and the synthetic human-type tridecapeptide (hTDP), Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His, corresponding to the N-terminal sequences of hANG, were used to determine the species specificity of recombinant hREN (rhREN) and mREN. While hTDP was cleaved by both rhREN with similar Km and with the same order of kcat, rhANG was cleaved by mREN with 16.7-fold higher Km and with 28.2-fold lower kcat than by rhREN. These results showed that kcat/Km value of mREN for rhANG was 468-fold lower than that for rhREN acting on rhANG.

Eriko Takimoto

Papers

Angiotensinogen-deficient mice with hypotension.

Angiotensin II Type 1a Receptor-deficient Mice with Hypotension and Hyperreninemia

Chimeric renin-angiotensin system demonstrates sustained increase in blood pressure of transgenic mice carrying both human renin and human angiotensinogen genes

Hypertension Induced in Pregnant Mice by Placental Renin and Maternal Angiotensinogen

Comparative studies on species-specific reactivity between renin and angiotensinogen.