**4. Angiotensin II**

The renin-angiotensin aldosterone system is an endocrine system responsible for regulating normal blood pressure *in vivo*, through the regulation of extracellular volume, vascular structure, and integrity, maintaining homeostasis [27, 28]. One of its main components is angiotensin II (Ang II), a vasoactive octapeptide responsible for several actions in tissues [29].

Two subtypes of Ang II receptors have been identified in humans, ATR1 and ATR2, described as receptors formed by seven transmembrane domains coupled to the G protein (**Figure 7**), with ATR1 being the dominant subtype and being widely distributed in the endocrine, renal, cardiac, and nervous systems [30]. While ATR2, after birth, has low expression, persisting only in some organs, such as the brain, kidney, and peripheral vasculature, mediating the physiological effects of Ang II, and may increase its expression in pathological conditions, such as hypertension, cardiac, and renal failure [28, 31].

There are studies about signaling pathways and the action of angiotensin in different cell types, however, there is little information in the literature about the actions of Ang II receptors on erythrocytes and their signaling, especially considering human erythrocytes.

#### **Figure 7.**

*Angiotensin II synthesis. Angiotensinogen is converted into angiotensin I by renin that in turn is converted into angiotensin II by the angiotensin converting enzyme. Angiotensin II can bind to ATR1 and ATR2.*

*In vitro* experiments, carried out in 1997, showed a stimulatory effect of Ang II on erythropoiesis when erythroid progenitors were cultured in the presence of erythropoietin, demonstrating the importance of erythropoietin in erythropoiesis. Erythropoietin is an essential hormone for the regulation of erythropoiesis [32]. They also observed that the use of losartan (ATR1 antagonist, used to prevent vasoconstriction and volume expansion induced by circulating Ang II) blocked this stimulatory effect, demonstrating that Ang II, *via* the AT1 receptor, is responsible for mediating this stimulation [33, 34].

Reinforcing previous results in 2005, it was demonstrated that persistent activation of the renin-angiotensin system increases erythropoiesis in mice, *in vivo*, and that the most important receptor subtype responsible for this erythropoiesis was the AT1 receptor [35]. In 2015, in addition to reinforcing the idea that erythropoiesis and blood pressure are negatively regulated by inhibiting the ATR1 receptor, it was possible to say that the signaling pathways involved are complex and distinct since erythropoiesis is more resistant to inhibition of the ATR1 receptor than blood pressure control [30].

Some studies on the Ang II signaling pathway in erythrocytes have been described in order to elucidate the mechanism of the parasitic invasion of *Plasmodium falciparum* in erythrocytes. Research published in 2011 demonstrated that human erythrocytes express different Ang II receptors, namely ATR1, ATR2, and MAS receptors [36].

The levels of bradykinin (BK) and Ang- (1–7) increase in the presence of captopril (ECA inhibitor) in the supernatant of infected erythrocytes, decreasing parasite invasion and reducing PKA activity, through the association of receptors B2/MAS [37]. Thus, inhibition of protein kinase A (PKA) by the MAS receptor appears to be favorable to the erythrocyte against parasitic invasion.

Experiments in mice and humans showed that the activation of the ADORA2B-AMPK cascade, in the presence of angiotensin II, increased BPG mutase and consequently 2,3BPG, being beneficial for renal hypoxia, injury, proteinuria, and reduction of chronic kidney disease (CKD) [38].

In 2021, Guimares-Nobre and collaborators demonstrated that AT1 receptors and AT2 receptors, expressed in human erythrocytes, are capable of responding to osmotic stress situations in the presence of Ang II and its antagonists, losartan (ATR1 antagonist) and PD123319 (ATR2 antagonist). The study was carried out using modulators of signaling pathways, already recognized as activated by Ang II, in other cell types. As a result, it was possible to observe that, in osmotic stress, Ang II binds to the ATR2 receptor and reduces hemolysis through the PI3K/AKT and P38 pathways. However, when binding to ATR1, this protection did not occur (**Figure 8**) [39].

Furthermore, *ex vivo* experiments displayed that sickle cell erythrocytes treated with Ang II present increased cell deformability, decreased phosphatidyl serine translocation to the outer layer, and decreased hemoglobin S polymerization. All these factors are crucial findings for sickle cell disease outcomes (**Figure 9**) [40]. However, despite knowing this important action of Ang II in sickle cell erythrocytes, the precise mechanism of actions has not yet been demonstrated.

There is very little information regarding the importance of angiotensin II receptors on erythrocytes and the signaling pathways are triggered by it; however, researchers have been demonstrating that these receptors are functional and interfere in the survival of erythrocytes. Therefore, more studies are needed to expand this knowledge.

*Hormones Action on Erythrocytes and Signaling Pathways DOI: http://dx.doi.org/10.5772/intechopen.110096*

*The Erythrocyte - A Unique Cell*
