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

Abstract

The involvement and relevance of the renin–angiotensin system have been established clearly in cardiovascular diseases, and renin–angiotensin system involvement has also been investigated extensively in the central nervous system. Angiotensin II acts classically by binding to the AT 1 and AT 2 receptors. However, other pathways within the renin–angiotensin system have been described more recently, such as one in which angiotensin-(1–7) (Ang-(1–7)) binds to the receptor Mas. In the central nervous system specifically, it has been reported that this heptapeptide is involved in learning and memory processes that occur in central limbic regions, such as the hippocampus. Therefore, this prompted us to investigate the possible role of the Ang-(1–7)–receptor Mas pathway in epileptic seizures, which are also known to recruit limbic areas. In the present study, we show that Ang-(1–7) is the main metabolite of angiotensin I in rat hippocampi, and, strikingly, that thimet oligopeptidase is the main enzyme involved in the generation of Ang-(1–7). Furthermore, elevations in the levels of thimet oligopeptidase, Ang-(1–7), and of receptor Mas transcripts are observed in chronically stimulated epileptic rats, which suggest that the thimet oligopeptidase–Ang-(1–7)–receptor Mas axis may have a functional relevance in the pathophysiology of these animals. In summary, our data, which describe a new preferential biochemical pathway for the generation of Ang-(1–7) in the central nervous system and an increase in the levels of various elements of the related thimet oligopeptidase–Ang-(1–7)–receptor Mas pathway, unveil potential new roles of the renin–angiotensin system in central nervous system pathophysiology.

Update on the Angiotensin Converting Enzyme 2-Angiotensin (1–7)-Mas Receptor Axis: Fetal Programing, Sex Differences, and Intracellular Pathways

“…Interestingly, these investigators reported higher expression of this peptidase and the Mas receptor in a rat model of temporal lobe epilepsy suggesting a possible role of the Ang-(1-7)-Mas axis in this central pathology (28). Indeed, the study supports earlier reports of the direct processing of Ang I to Ang-(1-7) by thimet oligopeptidase in vascular smooth muscle cells and a rat hindlimb perfusion system (29,30).…”

Deficiency of angiotensin-converting enzyme 2 causes deterioration of cognitive function

“…8 Furthermore, the level of Ang-(1–7) was detected from the hippocampus using high-performance liquid chromatography assay and increased during the acute and silent phases of pilocarpine-induced epilepsy. 12 Pereira et al 13 show that Ang-(1–7) is the main metabolite of Ang I in rat hippocampi. These results also suggest that the ACE2/Ang-(1–7)/Mas receptor axis in the brain is essential for cognitive function.…”

The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

“…In addition, in Mas Ϫ/Ϫ mice, ANG-(1-7) concentrations are increased in the whole hippocampus, as well as in the CA1 area, suggesting the need for a functional ANG-(1-7)/MAS axis for normal ORM processing (299). Interestingly, it has been reported that in this brain region ANG-(1-7) can be formed independent of ANG II processing (417). Despite this evidence, the role of ANG-(1-7)/MAS axis in limbic-dependent memories remains poorly understood.…”