Structural biology

On stress and pressure

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The protein angiotensinogen must undergo conformational changes to be cleaved into a precursor of the hormone angiotensin, which increases blood pressure. Oxidative stress seems to mediate this structural alteration. See Letter p.108

Numerous signals emanating from the kidney, blood vessels, heart and brain regulate blood pressure, with an imbalance between them causing altered blood pressure. One such prominent signalling pathway is the renin–angiotensin system. Renin is a protease enzyme that catalyses the rate-limiting step in this pathway — cleavage of ten amino-acid residues at the amino terminus of its only known substrate, angiotensinogen. The resulting peptide is further processed into a family of angiotensin peptide hormones, the best characterized of which, angiotensin II, increases blood pressure in various ways. On page 108 of this issue, Zhou et al.1 provide structural evidence for the way in which redox-based conformational changes in angiotensinogen expose the site cleaved by renin.

The renin–angiotensin system is evolutionarily 'thrifty'2: the common outcome of angiotensin activity is sodium conservation. In an ancient environment in which sodium was scarce, angiotensin activity may have been beneficial. However, the system can have detrimental effects in the modern, sodium-replete environment. Indeed, the sodium-preserving actions of angiotensin are problematic for the large population of salt-sensitive people with high blood pressure (hypertension), and drug-mediated blockade of the renin–angiotensin system is of clinical importance because it can be an effective treatment for many people with hypertension3.

Although angiotensin can activate diverse cellular processes on binding to its cellular receptors, a common thread is the generation of reactive oxygen species4. For instance, activation of angiotensin receptors can promote the generation of superoxide and induces oxidative stress in the main cardiovascular target organs such as the kidney, blood vessels and brain. (Oxidative stress results from an imbalance between the production of reactive oxygen species and the system's ability to readily detoxify reactive intermediates.) Superoxide is a highly reactive free radical that can be converted to lipid-soluble reactive products, including hydrogen peroxide and peroxynitrite. The link between the renin–angiotensin system and superoxide has been established both pharmacologically and genetically. In fact, treatment with antioxidants can lower blood pressure in rat and mouse models of angiotensin-induced hypertension. Such findings further support the pro-hypertensive effects of reactive oxygen species as a downstream effector of the renin–angiotensin system.

One consequence of oxidative stress is chemical modification of proteins at cysteine amino-acid residues. Interaction between hydrogen peroxide and the thiol group on cysteines results in the formation of a sulphenic-acid intermediate that can react with nearby cysteines to form disulphide bonds, altering a protein's structure and activity. But what is the link between oxidative alterations to proteins and hypertension? Zhou et al.1 provide a glimpse of the answer.

The authors present the crystal structure of angiotensinogen at a resolution of 2.1 ångströms and show that the cleavage site for angiotensin generation is inaccessibly buried inside the protein's amino-terminal tail (Fig. 1). To identify the conformational changes required to make this site accessible to renin, they also solved the crystal structure of the initiating complex. This consisted of genetically engineered angiotensinogen and a catalytically inactive mutant of renin. The authors' analyses reveal that angiotensinogen's amino-terminal tail — including the angiotensin cleavage site — undergoes a conformational shift that makes it accessible to renin. The linchpin of this structural change seems to be the formation of a disulphide bridge between a pair of evolutionarily conserved cysteine residues (C18 and C138) in angiotensinogen.

Figure 1: The renin–angiotensin system.

Zhou et al.1 show that in the reduced form of angiotensinogen, the angiotensin peptide and the peptide's cleavage site (red/green) are inaccessibly buried. Reactive oxygen species (ROS) cause angiotensinogen oxidation and disulphide-bridge formation between the thiol (SH) groups of its C18 and C138 residues. This results in a conformational change that makes the angiotensin peptide and its cleavage site accessible to renin. The initial product formed by the renin–angiotensinogen cleavage reaction is the ten-amino-acid peptide angiotensin I (Ang I), which can be cleaved further by angiotensin converting enzyme (ACE) to angiotensin II (Ang II), a hormone commonly associated with hypertension.

The oxidized (disulphide-bridged) state of angiotensinogen correlated with the protein's increased affinity for renin, and so increased the production of angiotensin1. Intriguingly, these increases were particularly evident when renin was in complex with the prorenin receptor, a membrane-bound renin receptor of obscure physiological significance that has been reported5 to increase the catalytic activity of both renin and its inactive precursor prorenin.

Notably, Zhou et al. find that the C18–C138 disulphide bridge is redox sensitive: the antioxidant molecule glutathione breaks the sulphur–sulphur link to regenerate two thiol groups. This may be physiologically significant because endogenous nitric oxide, which is a potent dilator of blood vessels, thus reducing blood pressure, can alter cysteine thiols by means of S-nitrosylation (addition of a nitrogen monoxide group). Zhou et al. find that a nitric-oxide donor reacts with and blocks the thiols on C18 and C138, thereby possibly preventing further oxidation of the cysteine residues. This finding suggests that intracellular chemicals such as reactive oxygen species and nitric oxide can tightly regulate the redox state of angiotensinogen — and so its processing — in tissues. The implication is that the rate of angiotensin generation may be as much dictated by the redox states of the tissue and blood as by the absolute levels of renin and angiotensinogen.

Under normal conditions, there is roughly a 40:60 ratio of reduced-to-oxidized angiotensinogen in the circulation. Are the levels of oxidized angiotensinogen increased in hypertension? Yes, according to Zhou and colleagues. They demonstrate that the proportion of oxidized angiotensinogen was significantly higher in the blood plasma of 12 patients with pre-eclampsia — a syndrome of hypertension and increased levels of serum proteins in the urine during pregnancy. This is interesting in light of previous findings that a variant form of the gene encoding angiotensinogen is associated with hypertension6 and pre-eclampsia7.

We must now consider whether Zhou and co-workers' structural findings are applicable to common forms of hypertension. The investigators' observations suggest that angiotensin-induced production of reactive oxygen species results in a feed-forward mechanism favouring an ever-increasing activity of the renin–angiotensin system and its pro-hypertensive effects. Can this cycle be amplified by genetic variants that either promote additional angiotensinogen synthesis or favour its structurally active form?

The most commonly studied variant within the protein-coding regions of the angiotensinogen gene is located away from the functional moieties that Zhou et al.1 identify. However, this variant is linked to another one found in the promoter region of the angiotensinogen gene that enhances angiotensinogen production8,9. My laboratory has just shown10 in mice that the presence of both variants affects blood pressure only in animals on a high-salt diet — a condition that promotes oxidative stress. Therefore, given what is now known about the oxidation-associated changes in angiotensinogen, it would be intriguing to assess whether variants in the angiotensinogen gene affect the protein's redox-regulated activity under conditions that promote oxidative stress.


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Sigmund, C. On stress and pressure. Nature 468, 46–47 (2010) doi:10.1038/468046a

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