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Pfizer Cardiovascular Research, St. Louis Laboratories, Chesterfield, Missouri 63017
Address all correspondence and requests for reprints to: Charles W. Bolten, Pfizer Molecular Pharmacology, 700 Chesterfield Parkway, Chesterfield, Missouri 63017. E-mail: charles.w.bolten{at}pfizer.com.
Aldosterone control of sodium reabsorption in tight epithelia of the distal nephron is well established in classical endocrinology. However, identification of mineralocorticoid receptors (MR) in nonepithelial tissues such as the heart, vasculature, and brain has prompted an evolution of mineralocorticoid biology from a primarily nephrocentric focus toward a broader understanding of this system’s role in various cardiovascular pathologies. Important in this evolution was the observation that aldosterone has direct deleterious effects in nonepithelial tissues particularly when maintained at exposures inappropriate for salt status (1). There is now a plethora of experimental and clinical evidence indicating that one such affected organ is the heart (2). Numerous animal studies have demonstrated that mineralocorticoid excess in the presence of high salt leads to coronary vascular inflammatory lesions, endothelial dysfunction, and myocardial fibrosis (3). Clinically, it has been observed that plasma aldosterone levels correlate positively with the degree of cardiac damage (4). Moreover, demonstration that pharmacological treatment with an MR antagonist such as spironolactone or the more selective antagonist eplerenone reverses this cardiac damage further supports a role for the aldosterone-MR system in cardiac pathology. Yet despite existing evidence, our understanding of the molecular mechanisms by which MR activation leads to cardiac damage is still rudimentary. The microarray study by Turchin and colleagues (5) published in this issue of Endocrinology represents the most detailed report of acute MR gene regulation in the heart to date and begins to shed light on potentially important early MR-mediated mechanisms.
Nuclear receptors are ligand-gated transcription factors. Thus, a logical approach toward understanding the molecular mechanisms relevant to the downstream biology of MR is to identify direct target genes under control of the receptor. To this end, Turchin et al. (5) examined the temporal changes in cardiac gene expression in response to acute administration of a physiological dose of aldosterone in high-salt-fed, uninephrectomized mice. Using Cluster Analysis of Gene Expression Dynamics (CAGED), 12 genes showing significant changes in their temporal expression pattern were identified in hearts from aldosterone-injected mice. All 12 genes showed an initial, acute decrease in expression, followed by a rebound above baseline before eventually returning to baseline. Interestingly, no genes were identified that increased in expression throughout the duration of the experiment. This latter observation may in fact reflect the early pathological process or may be a consequence of using total RNA from whole-heart samples for analyses. In other organs such as the kidney, unraveling MR target gene regulation has been problematic because MR expression is localized to specific cell populations (6). Thus, traditional methods looking at RNA or protein readouts for potential target gene regulation may not overcome the dilution effect of the high percentage of nonrelevant cells. In the heart, MR is reportedly expressed in cardiomyocytes (7). Because these cells make up less than 25% of total cells within the adult mouse heart (8), it is possible that subtle changes in the temporal expression pattern of some genes were masked. Having said this, it would stand to reason that the 12 genes identified were those whose change in expression level was the greatest relative to control hearts and so may be critical early responses to acute MR activation.
As the authors state, phosphatases were predominant in the genes identified. Among these was protein phosphatase 5 (Ppp5), a serine/threonine protein phosphatase reported to participate in several cellular signaling pathways including those initiated by glucocorticoids (9) and oxidative stress (10). Ppp5 has been shown to associate with heat-shock protein 90 (Hsp90) and glucocorticoid receptor complexes containing Hsp90 (11). MR associates with Hsp90 when it is in an inactive state (12), thus suggesting that Ppp5 may also play a role in MR signaling. Phosphorylation is important in activation and transformation of steroid receptors (13). Alnemri et al. (14) reported that recombinant MR undergoes phosphorylation in vitro; this observation was then extended by Galigniana in 1998 (15). Using rat kidney MR, this investigator demonstrated that MR phosphorylation was important for ligand binding, whereas dephosphorylated MR was necessary for DNA interaction. Although Ppp5 was not among the panel of phosphatases examined in that study, one could speculate based on the current observations of Turchin et al. (5) that the early decrease in Ppp5 expression in hearts of aldosterone-injected mice would allow phosphorylated MR to bind aldosterone, whereas the subsequent increase in Ppp5 expression would dephosphorylate MR, thereby allowing DNA interaction. Similarly, changes in the temporal expression of other phosphatases identified by Turchin et al. (5) such as uteroglobin, which has antiinflammatory properties, fit mechanistically with our current empirical observations of aldosterone-induced cardiac damage, e.g. vascular inflammation as an early effect in the pathology.
MR antagonists have proven beneficial in the clinic for the treatment of hypertension and postmyocardial infarction/heart failure, as well as providing end-organ protection (16, 17). Identification of the serum- and glucocorticoid-regulated kinase (SGK-1) as an acute aldosterone-regulated protein that increases epithelial sodium channel (ENaC)-dependent sodium transport has provided significant insight into MR molecular mechanism in the distal nephron (18). Demonstration of impaired sodium retention in response to elevated aldosterone in SGK-1 knockout mice strengthened the relevance of MR-regulated SGK expression, and it is now widely accepted that direct regulation of SGK-1 is an important component of MR gene regulation in epithelial target cells (19). In keeping with the classical view of mineralocorticoid biology, many studies have focused on the kidney and distal colon as aldosterone target tissues, and regulation of several additional transcripts has been reported (18, 20, 21, 22). Two decades of research have significantly improved our understanding of MR gene regulation in the epithelia. In contrast, such enhanced understanding of MR gene regulation in nonepithelial cells has been comparably slow. However, studies such as the one by Turchin et al.(5) provide an interesting starting point for subsequent investigations into nonepithelial MR-regulated genes, thus increasing the likelihood of understanding tissue-specific MR effects.
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Abbreviations: Hsp90, Heat-shock protein 90; MR, mineralocorticoid receptor; Ppp5, protein phosphatase 5; SGK-1, serum- and glucocorticoid-regulated kinase.
Received May 1, 2006.
Accepted for publication May 3, 2006.
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