Review

Levels of angiotensin and molecular biology of the tissue renin angiotensin systems

The renin-angiotensin-aldosterone system (RAAS) is a specific hormonal cascade implicated in the blood pressure control and sodium balance regulation. Several components of this pathway have been identified including renin, angiotensinogen, angiotensin-converting enzyme, angiotensins with a wide range of distinct subtypes and receptors, and aldosterone. The RAAS is not only confined to the systemic circulation but also exists locally in specific tissues such as the heart, brain, and blood vessels with a particular paracrine action. Alteration of RAAS function can contribute to the development of hypertension and the emergence of its associated end-organ damage. Genotypic variations of the different genes of RAAS cascade have been linked to the susceptibility to essential hypertension. Accordingly, to understand the pathogenesis of essential hypertension and its related complications, deep insight into the physiological and genetic aspects of RAAS with its different components and pathways is necessary. In this review, we aimed to illustrate the physiological and genetic aspects of RAAS and the underlying mechanisms which link this system to the predisposition to essential hypertension.

Chronically elevated angiotensin II is a widely-established contributor to hypertension and heart failure via its action on the kidneys and vasculature. It also augments the activity of peripheral sympathetic nerves through activation of presynaptic angiotensin II receptors, thus contributing to sympathetic over-activity. Although some cells can synthesise angiotensin II locally, it is not known if this machinery is present in neurons closely coupled to the heart. Using a combination of RNA sequencing and quantitative real-time polymerase chain reaction, we demonstrate evidence for a renin-angiotensin synthesis pathway within human and rat sympathetic stellate ganglia, where significant alterations were observed in the spontaneously hypertensive rat stellate ganglia compared with Wistar stellates. We also used Förster Resonance Energy Transfer to demonstrate that administration of angiotensin II and angiotensin 1–7 peptides significantly elevate cyclic guanosine monophosphate in the rat stellate ganglia. Whether the release of angiotensin peptides from the sympathetic stellate ganglia alters neurotransmission and/or exacerbates cardiac dysfunction in states associated with sympathetic over activity remains to be established.

An athlete's potential to succeed at the highest level of sport may be determined in part by their physical resilience, such as their ability to recover quickly from training/competition, and their robustness regarding injury risk, particularly concerning muscle tissue. There is evidence to suggest that a high individual variability exists in (i) the response to exercise-induced muscle damage (EIMD) and (ii) muscle injury risk; and differences in genetic make-up might explain some of this variation. This chapter summarizes the current evidence regarding associations between genetic variation and the individual response following EIMD, and the risk of suffering muscle injuries. Further, this chapter proposes a new potential mechanical mechanism underlying skeletal muscle's maladaptation to strenuous exercise, thus providing a better understanding of the tissue-specific contribution to EIMD, exertional rhabdomyolysis and muscle strain injury.

The renin–angiotensin system (RAS) is a key regulator of blood pressure and blood volume homeostasis. The RAS is primarily comprised of the precursor protein angiotensinogen and the two proteases, renin and angiotensin-converting enzyme (ACE). Angiotensin I (Ang I) is derived from angiotensinogen by renin, but appears to have no biological activity. In contrast, angiotensin II (Ang II) that has a variety of biological functions in the cells is converted from Ang I through removal of two-C-terminal residues by ACE. The physiological effects of Ang II are due to Ang II signaling through specific receptor binding, resulting in muscle contraction leading to increased blood pressure and volume. To modulate RAS, three classes of drugs have been developed: (1) renin inhibitors to prevent angiotensinogen conversion to Ang I, (2) ACE inhibitors, to prevent Ang I processing to Ang II and (3) angiotensin receptor blockers, to inhibit Ang II signaling through its receptor. Studies using the RAS inhibitors and Ang II demonstrated that RAS signaling mediates actions of Ang II in the regulation of proliferation and differentiation of specific hematopoietic cell types, especially in the red blood cell lineage. Accumulating evidence indicates that RAS regulates EPO, an essential mediator of red cell production, for human anemia and erythropoiesis in vivo and in vitro. The regulation of EPO expression by Ang II may be responsible for maintaining red blood cell homeostasis. This review highlights the biological roles of RAS for blood cell and EPO homeostasis through Ang II signaling. The molecular mechanism for Ang II-induced EPO production of the cell or tissue type-specific expression is discussed.

Angiotensin II (Ang II) plays an important role in the regulation of the T-cell response during inflammation. However, the cellular mechanisms underlying the regulation of lymphocytes under physiologic conditions have not yet been studied. Here, we tested the influence of Ang II on T-cell migration using T cells from BALB/c mice. The results obtained in vivo showed that when Ang II production or the AT₁ receptor were blocked, T-cell counts were enhanced in blood but decreased in the spleen. The significance of these effects was confirmed by observing that these cells migrate, through fibronectin to Ang II via the AT₁ receptor. We also observed a gradient of Ang II from peripheral blood to the spleen, which explains its chemotactic effect on this organ. The following cellular mechanisms were identified to mediate the Ang II effect: upregulation of the chemokine receptor CCR9; upregulation of the adhesion molecule CD62L; increased production of the chemokines CCL19 and CCL25 in the spleen. These results indicate that the higher levels of Ang II in the spleen and AT₁ receptor activation contribute to migration of naive T cells to the spleen, which expands our understanding on how the Ang II/AT₁ receptor axis contributes to adaptive immunity.

Major areas controlling sexual motivation and performance in males include the mesolimbic dopamine (DA) system, the medial preoptic area (MPOA), the amygdala, and the bed nucleus of the stria terminalis (BST). Genital reflexes are controlled by the MPOA, paraventricular nucleus (PVN), brainstem, and spinal cord areas. Mating is integrated by the MPOA, amygdala, BST, PVN, and mesolimbic and nigrostriatal tracts, which are also important for other social behaviors. Perinatal and adult hormones predispose the network to produce specific behaviors. Steroid hormones have primarily slow, genomically mediated effects, although they may also have rapid effects mediated by membrane receptors.