α 2-Adrenoceptors: Challenges and Opportunities-Enlightenment from the Kidney

Abstract

It was indeed a Don Quixote-like pursuit of the mechanism of essential hypertension when we serendipitously discovered α ₂-adrenoceptors (α ₂-ARs) in skin-lightening experiments in the frog. Now α ₂-ARs lurk on the horizon involving hypertension causality, renal denervation for hypertension, injury from falling in the elderly and prazosin's mechanism of action in anxiety states such as posttraumatic stress disorder (PTSD). Our goal here is to focus on this horizon and bring into clear view the role of α ₂-AR-mediated mechanisms in these seemingly unrelated conditions. Our narrative begins with an explanation of how experiments in isolated perfused kidneys led to the discovery of a sodium-retaining process, a fundamental mechanism of hypertension, mediated by α ₂-ARs. In this model system and in the setting of furosemide-induced sodium excretion, α ₂-AR activation inhibited adenylate cyclase, suppressed cAMP formation, and caused sodium retention. Further investigations led to the realization that renal α ₂-AR expression in hypertensive animals is elevated, thus supporting a key role for kidney α ₂-ARs in the pathophysiology of essential hypertension. Subsequent studies clarified the molecular pathways by which α ₂-ARs activate prohypertensive biochemical systems. While investigating the role of α ₁-adrenoceptors (α ₁-ARs) versus α ₂-ARs in renal sympathetic neurotransmission, we noted an astonishing result: in the kidney α ₁-ARs suppress the postjunctional expression of α ₂-ARs. Here, we describe how this finding relates to a broader understanding of the role of α ₂-ARs in diverse disease states. Because of the capacity for qualitative and quantitative monitoring of α ₂-AR-induced regulatory mechanisms in the kidney, we looked to the kidney and found enlightenment.

Figure 1

Distribution of α-adrenoceptors. Illustration summarizes our conclusion that normally α₁-ARs dominate the postjunctional membrane in the neuroeffector junction (a); however, following chronic treatment with an α₁-AR antagonist or in genetic hypertension, α₂-ARs become the dominant α-adrenoceptor subtype residing within the postjunctional membrane (b). In both cases, α₂-ARs are also localized to the prejunctional and extrajunctional membranes. This model was tested using subpressor levels of renal sympathetic nerve stimulation (RSNS) with sodium excretion as the outcome measure and, therefore, applies to sympathetic regulation of sodium reabsorption by renal epithelial cells; however, we hypothesize that similar changes in α₂-ARs may occur in the renal vasculature and may contribute to sodium retention and hypertension. The dotted line (-----) denotes a diffusion barrier that hampers the entry of norepinephrine (NE) into the neuroeffector junction.

Figure 2

Signaling mechanisms in the SHR renal microcirculation. Renal sympathetic nerves release norepinephrine which stimulates α₂-adrenoceptors (α₂-ARs) in renal vascular smooth muscle cells, thus leading to dissociation of G_i and release of α_i and βγ subunits. Angiotensin II engages type 1 angiotensin II receptors (AT₁-Rs) which results in the release of α_q from G_q. βγ subunits arising from G_i-coupled α₂-ARs bind receptor for activated C kinase 1 (RACK1) and localize this scaffolding protein to the cell membrane. At the cell membrane, RACK1 also binds phospholipase C (PLC) and protein kinase C (PKC), and PLC binds α_q. Together, these interactions result in an efficient signaling complex in which activation of PLC by α_q is enhanced by the simultaneous binding of βγ subunits to PLC. Thus, PLC serves as a coincident detector, whereas RACK1 functions here to bring together the stimulating components of this coincident signaling mechanism. This coincident signaling mechanism is further amplified by the fact that RACK1 localizes PLC with PKC, thus facilitating the activation of PKC, which mediates contraction of vascular smooth muscle cells. In addition to βγ-mediated signaling, release of α_i by α₂-ARs inhibits the adenylate cyclase/cAMP pathway, which further increases contraction of vascular smooth muscle cells. Because of the increased pool of G_i-coupled α₂-ARs, both the α_i-mediated and βγ-mediated mechanisms are more engaged in the SHR renal microvasculature, thus leading to renal vasoconstriction, sodium retention, and hypertension. The model was tested using pressor levels of angiotensin II with renovascular responses (or in some experiments contractile responses to isolated preglomerular vascular smooth muscle cells) as the outcome measure and, therefore, applies to sympathetic regulation of renal vascular smooth muscle cells; however, we hypothesize that similar coincident signaling involving α₂-ARs may occur in renal epithelial cells and may contribute directly to sodium retention and hypertension independent of renovascular changes.