Involvement of insulin-regulated aminopeptidase in the effects of the renin–angiotensin fragment angiotensin IV: a review

Abstract

For decades, angiotensin (Ang) II was considered as the end product and the only bioactive peptide of the renin-angiotensin system (RAS). However, later studies revealed biological activity for other Ang fragments. Amongst those, Ang IV has drawn a lot of attention since it exerts a wide range of central and peripheral effects including the ability to enhance learning and memory recall, anticonvulsant and anti-epileptogenic properties, protection against cerebral ischemia, activity at the vascular level and an involvement in atherogenesis. Some of these effects are AT(1) receptor dependent but others most likely result from the binding of Ang IV to insulin-regulated aminopeptidase (IRAP) although the exact mechanism(s) of action that mediate the Ang IV-induced effects following this binding are until now not fully known. Nevertheless, three hypotheses have been put forward: since Ang IV is an inhibitor of the catalytic activity of IRAP, its in vivo effects might result from a build-up of IRAP's neuropeptide substrates. Second, IRAP is co-localized with the glucose transporter GLUT4 in several tissue types and therefore, Ang IV might interact with the uptake of glucose. A final and more intriguing hypothesis ascribes a receptor function to IRAP and hence an agonist role to Ang IV. Taken together, it is clear that further work is required to clarify the mechanism of action of Ang IV. On the other hand, a wide range of studies have made it clear that IRAP might become an important target for drug development against different pathologies such as Alzheimer's disease, epilepsy and ischemia.

Cardioprotective Angiotensin-(1–7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor

“…Despite accumulating evidence of Ang IV action through insulin-regulated aminopeptidase, our results also support the notion that several Ang IV physiological effects could be mediated through AT1-R. 11,45,46 Hence, depending on its concentration in physiological or pathophysiological situations, Ang IV can act as an efficient AT1-R agonist. Of note, Ang IV, which lacks the first 2 N-terminal amino acids of Ang II (Table S2), is sufficient for producing full agonism on both G-protein and β-arr recruitment, in line with previous structure/function studies.…”

Angiotensin II–Independent Angiotensin-(1–7) Formation in Rat Hippocampus

“…38 Additional studies have demonstrated that AngIV (which is produced via AngII degradation) has both anticonvulsant and antiepileptic effects. 39 In a previous study, we found evidence of upregulation of ACE and of the AT 1 receptor in the hippocampi of WARs with TLE, and we showed that blockage of the AT 1 receptor by systemic administration of the antagonist losartan significantly decreased the severities of seizures, therefore suggesting a key role for AngII. 28 Nevertheless, as described above, we surprisingly found Ang-(1-7) to be the main metabolite generated after AngI degradation, whereas AngII formation was not detected.…”

Local expression of AP/AngIV/IRAP and effect of AngIV on glucose-induced epithelial transport in human jejunal mucosa

“…21,22 Some of the effects of AngIV may be mediated by an interaction with AT1R and/or AT2R, or by a mixture of all three receptors (AT1R, AT2R, IRAP), possibly depending on tissue type and expression pattern. 22 Thus, the present results cannot exclude the possibility that the effects of AngIV are mediated via the AT2R in line with our previous work showing that AT2R activation increased the glucose-induced electrogenic response in a similar setting. 14 Pharmacological analyses using stable and highly selective AngIV analogs that have been developed should considerably improve the outcomes of future studies.…”