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    • Studies have demonstrated that AT plays

    2023-02-06

    Studies have demonstrated that AT2 plays a greater role in modulating arterial pressure in females than in males. Chronic low-dose infusion of Ang II decreased blood pressure in female rats at a dose that had negligible effects in males. Furthermore, AT2 blockade eliminates the depressor response to Ang II, confirming the vasodepressor role of the AT2 in females (Sampson et al., 2008). Similarly, while Ang II infusion results in a mild increase in blood pressure in WT male and AT2R-KO female mice, the Ang II pressor response in WT female mice is attenuated. In this group of mice, renal expression of AT2 was 3-fold greater in WT females than in WT males under basal conditions and after chronic Ang II. Furthermore, when renal sensitivity to Ang II was investigated, it was seen that Ang II increased tubuloglomerular feedback sensitivity in both male genotypes and the female AT2-KO group but had no apparent effect in female WT mice. This attenuated pressor response and resetting of tubuloglomerular feedback to Ang II in AT2 intact females gives support for a protective role of AT2 against the prohypertensive effects of Ang II in females. In line with this, greater renal cortical levels of Ang(1–7) have been identified in female versus male spontaneously hypertensive rats, both basally and after exogenous Ang II infusion. Furthermore, Sullivan et al. (2010) also demonstrated an increase in Mas expression in the renal CID 2745687 mg following Ang II infusion only in female spontaneously hypertensive rats. Hence, these results provide evidence of a shift in the renal vasoconstrictor/vasodilator ratio of the RAS toward vasodilation in females, with clear sex differences in the renal hemodynamic response to Ang II. However, are these differences among male and female due only to hormonal activational effects? Although previous data have indicated an undisputed impact of the circulating (activational) effects of sex hormones on sexually dimorphic cardiovascular responses (Hay et al., 2014, Sampson et al., 2012a, Sampson et al., 2012b, Xue et al., 2014), in the present study we found that SCC also modulates basal Agtr1a, Agtr2 and Mas1 receptor dimorphic gene expression in the renal cortex in isolation of organizational and activational hormonal effects. As previously shown by Brown et al. (2012), no differences in renal AT1R between male and female mice were observed either in XX-SCC or XY-SCC mice. However, our results identified a sex chromosome effect for both Agtr2 and Mas1 gene expression in the renal cortex. Regardless of sex (male or female), XX-SCC mice express higher levels of mRNA Agtr2 and Mas1 gene expression than XY-SCC mice, therefore showing a shift of the balance of the RAS to the depressor arm in XX-SCC mice. As AT2 and Mas receptors have been implicated as modulators of natriuresis (Gross et al., 2000, Siragy et al., 1999) and both receptors are upregulated in XX-SCC mice in the renal cortex (Sampson et al., 2008, Silva-Antonialli et al., 2004), this may result in a differential pressure-natriuresis relationship, contributing to sex-associated differences in long-term blood pressure regulation. The approach of this study was focused on the analysis of angiotensin receptor gene expression, however some limitations should be taken into consideration. Mice were gonadectomized in late puberty and 15 days later gene expression of different brain and kidney tissue were analyzed. Although preliminary results demonstrate a dramatically reduction in estradiol and testosterone levels we cannot exclude a possible sex hormone effect in the analyzed phenotypes. Furthermore we were not able to confirm the translation to protein. Although this was intended, previous studies have tested available commercial AT1 and AT2 antibodies and have demonstrated to be nonspecific. The immunostaining patterns observed were different for every antibody tested, and were unrelated to the presence or absence of AT1 receptor since identical bands were observed in wild-type mice and in AT1A and AT2 knock-out mice not expressing the target protein. Thus, from those studies it is conclude that none of the commercially available AT1 and AT2 receptor antibodies tested upon the present meet the criteria for specificity and if used may lead to erroneous physiological interpretations and conclusions (Benicky et al., 2012, Hafko et al., 2013, Herrera et al., 2013).