Angiotensin II Type 2 Receptor and Receptor Mas Are Colocalized and Functionally Interdependent in Obese Zucker Rat Kidney

Abstract

The actions of angiotensin II type 2 receptor (AT2R) and the receptor Mas (MasR) are complex but show similar pro-natriuretic function; particularly AT2R expression and natriuretic function are enhanced in obese/diabetic rat kidney. In light of some reports suggesting a potential positive interaction between these receptors, we tested hypothesis that renal AT2R and MasR physically interact and are inter-dependent to stimulate cell signaling and promote natriuresis in obese rats. We found that infusion of AT2R agonist C21 in obese Zucker rats (OZR) increased urine flow (UF) and urinary Na-excretion (UNaV) which were attenuated by simultaneous infusion of the AT2R antagonist PD123319 or the MasR antagonist A-779. Similarly, infusion of MasR agonist Ang-(1-7) in OZR increased UF and UNaV, which were attenuated by simultaneous infusion of A-779 or PD123319. Experiment in isolated renal proximal tubules of OZR revealed that both the agonists C21 and Ang-(1-7) stimulated NO which was blocked by either of the receptor antagonists. Dual-labeling of AT2R and MasR in OZR kidney sections and human proximal tubule epithelial cells showed that AT2R and MasR are colocalized. The AT2R also co-immunoprecipitated with MasR in cortical homogenate of OZR. Immunoblotting of cortical homogenate cross-linked with zero length oxidative (sulfhydryl groups) cross-linker cupric-phenanthroline revealed a shift of AT2R and MasR bands upward with overlapping migration for their complexes which were sensitive to the reducing β-mercaptoethanol, suggesting involvement of –SH groups in cross linking. Collectively, the study reveals that AT2R and MasR are co-localized and functionally interdependent in terms of stimulating NO and promoting diuretic-natriuretic response.

Interaction between Angiotensin Type 1, Type 2, and Mas Receptors to Regulate Adult Neurogenesis in the Brain Ventricular–Subventricular Zone

“…This suggests a functional dependence between AT2 and MasR for the AT2-induced generation of neurospheres. Accumulating evidence shows that both receptors are co-localized, form heterodimers, and have different functional interactions in different cells and experimental conditions [27,[95][96][97], and recent data from our laboratory (unpublished) showed that young AT2-KO mice show a reduced expression of MasR in the substantia nigra and striatum, which may also contribute to the decrease in proliferation and neurogenesis observed in the V-SVZ of AT2-KO mice. Therefore, although RAS receptors have been associated with different cellular and physiological responses, their role in neurogenesis is complex, as shown by the present results that reveal the presence of AT1, AT2, and MasR interactions possibly both in physiological or pathological situations.…”

Angiotensin‐(1‐7) mitigated angiotensin II‐induced abdominal aortic aneurysms in apolipoprotein E‐knockout mice

“…We and others have demonstrated that the protective effects of Ang‐(1‐7) on atherosclerosis were largely blocked by A779 (Yang et al, ) or PD123319 (Tesanovic et al, ). Recently, AT 2 and Mas receptors were found to share 31% sequence identity (Villela et al, ), and these two receptors were colocalized and functionally interdependent in obese Zucker rat kidney (Patel, Ali, Samuel, Steckelings, & Hussain, ). More recently, Leonhardt et al elegantly demonstrated the formation of heterodimers of Mas and AT 2 receptors and thus inhibition of one of the heterodimer partners may cause inhibition of the other (Leonhardt et al, ).…”

Renin-angiotensin-system, a potential pharmacological candidate, in acute respiratory distress syndrome during mechanical ventilation

“…There has been considerable interest in the balance between ACE/Ang-II/AT1R axis and the ACE2/Ang-(1-7)/ MasR axis in blood pressure homeostasis and cardiovascular function (as shown in Figure-1). Interestingly, AT2R is normally induced by activation of the ACE2/Ang-(1-7)/MasR axis, while more recent evidence suggests that Ang-(1-7) may activate AT2R to antagonize AT1Rmediated effects [23,24].…”