Deoxycorticosterone (DOC) was the first steroid with significant mineralocorticoid action to be discovered. It was synthesized more than a decade before the more potent primary mineralocorticoid aldosterone was isolated.1 The propensity for excessive amounts of DOC and its inactive acetate, DOCA, to produce hypertension and cardiovascular pathology was noted soon after they began to be used as lifesaving therapy for patients with Addison's disease.2 Aldosterone and DOC act on the mineralocorticoid receptor (MR) in the epithelia of mammalian kidney and colon to increase sodium and other cation transport, their mineralocorticoid effect. In addition, diverse studies since the 1950s demonstrate that MRs are expressed in nonepithelial cells, including cardiovascular cells (cardiac myocytes and vascular smooth muscle fibroblasts), central nervous system (select neurons, microglia, and astrocytes), and immune cells where they mediate diverse cell-type–specific effects. Some of these effects increase the blood pressure independently of renal effects through direct effects on the heart and vessels that increase contractility, tissue repair, and hypertrophy and structures in the brain that modulate the sympathetic nervous system activity.1,2 Evidence from a large number of basic and clinical studies that inappropriate activation of MR results in inflammation and cardiovascular remodeling independently of hypertension culminated in the seminal clinical RALES study that demonstrated that heart failure patients benefit from MR antagonists at doses too low to decrease their blood pressure.1 Studies since then have made the use of MR antagonists, a standard adjunct in the treatment of heart failure and pathological end-organ sequelae of metabolic syndrome and diabetes,2 and have led to the development of nonsteroidal MR antagonists with fewer side effects.3 However, MRs are critical for many functions, including normal cognition, memory, and mood.2,4 Therapeutic agents that target specific deleterious MR-mediated functions would spare critical MR actions. The intriguing and potentially very important findings described in the paper by Bal et al5 may provide the basis for such an agent.
This article on the ameliorative effects of LXR activation also illustrates the complexity of the classical, yet often misunderstood, model of DOCA salt. It is neither a “pure” model of hypertension, nor equivalent to a simple mineralocorticoid-salt excess. DOC action and metabolism are different from those of aldosterone. Moreover, in this model, the decrease in renal mass by uninephrectomy further deranges the renin–angiotensin–aldosterone system.
Because of its significantly lower cost compared with aldosterone, deoxycorticosterone acetate (DOCA) was and is still used experimentally as a mineralocorticoid. DOCA is inactive; its conversion to DOC by esterases occurs with variable efficiently depending on the tissue and is slow in some tissues, particularly muscle.6 In vivo actions of DOC differ from those of aldosterone. DOC normally circulates in low concentrations that do not modulate the MR of the renal tubules as aldosterone does due to its inactivation in the renal tubule epithelia by 20-ketosteroid reductase, an isozyme of the human AKR1C3 gene also involved in androgen metabolism.6 Therefore, although DOC has an in vitro affinity for the MR similar to aldo, cortisol, and corticosterone, normally the activity of DOC in vivo in the kidney is approximately 2% that of aldo. DOC has a renal mineralocorticoid effect only when used at high enough doses to saturate the AKR1C3 isozyme. As most tissues do not express AKR1C3, doses of DOC that increase sodium transport in the kidney are far beyond its physiological range (Fig. 1), thus have proportionately greater effects upon MR not protected by AKR1C3 in the rest of the body.
At high concentrations, higher than those attained even in primary aldosteronism, aldosterone and DOC activate the glucocorticoid receptor (GR) in vitro,7 a fact to be considered when interpreting experimental results involving supraphysiological amounts of mineralocorticoids, including DOCA, in which hydrolysis to produce the active steroid DOC and inactivation by AKR1C3 is uneven across tissues. DOC concentrations in some tissues, including the heart, are high relative to the concentrations in the kidney.
MR and GR interact at several levels , as is depicted in Figure 1. Both are steroid hormone nuclear transcription factors that form homodimers and heterodimers with each other to bind hormone response elements (HREs) on the DNA to start gene transcription and share many HREs and some requisite cotranscription factors.1 Although MR generally is an activator of transcription, GR may activate or suppress transcription depending on the gene and cotranscription factors. Little is yet known about the efficiency of MR:GR heterodimers compared with homodimers on the transcription of all but a few of their many gene targets. MR and GR functions may be synergistic or in opposition. MR- and GR-mediated transcriptional activities tend to be in opposition for genes related to proliferation, inflammation, and repair/fibrosis, with the MR stimulating these functions. As an example, it was reported in the early 1950s that DOCA treatment for Addison's disease exacerbated symptoms of rheumatoid arthritis, and that these signs improved with the concomitant administration of cortisone.8 In light of present knowledge of the importance of MR:GR interactions at multiple levels, it is important to reinterpret the literature that assumed that DOC is interchangeable with aldosterone, and that the DOCA-salt model is equivalent to aldosterone excess, especially in nonepithelial tissue.
MRs interact directly in the various cells of the heart to modulate the transcription of genes related to the generation of reactive oxygen species, inflammation, and fibrosis measured in the article by Bal et al describing the attenuation of DOCA-salt pathology by an LXR agonist. MR-mediated activity also modulates ion transport, membrane potential, and contractility in the cardiomyocyte.1,2 LXR is a steroid hormone nuclear transcription factor that shares many similarities with the MR and GR and is involved in both the de novo synthesis of glucocorticoids by the adrenal cortex and the intracellular reduction of cortisone and 11-dehydrocorticosterone to the active cortisol and corticosterone, respectively.9 LXR activation suppresses inflammatory markers in macrophages of adipose tissue, many of which are increased by MR activation.10 Thus, it is likely that GW3965 activation of the LXR attenuated cardiac functional and structural changes produced by DOCA through direct effects on gene transcription in multiple cell types in the heart independently of its effect on the hypertension in this model. Reduction of hypertension by the LXR agonist is also of great interest, as it may involve both peripheral and central effects. Functional MRs in macrophages are essential for several forms of hypertension, including DOCA salt excess, as well as metabolic syndrome.11 MR activates and LXR suppresses inflammatory transcripts in macrophages.10,12 Thus, targeting select functions of the LXR in macrophages may yield a new avenue for treatments for multiple aspects of the burgeoning epidemic of obesity-related diseases.
In summary, the current report by Banu Bal et al presents evidence that activation of the LXR is a potentially useful therapeutic intervention in pathological cardiac inflammation and remodeling due to DOCA-salt excess. Both the mineralocorticoid and glucocorticoid receptors may be involved, with GR-mediated mechanisms either synergizing or opposing those controlled by the MR. Although hypertension may have had a role, notwithstanding the title of the article, the transcription of genes responsible for oxidative stress, inflammation, and fibrosis leading to cardiac remodeling is increased by MR and suppressed by LXR activation. Future studies with a less complex and more physiological models should demonstrate the potential for LXR agonists in the treatment of disease in which inappropriate activation of the MR and/or GR are causal. In particular, it will be important to elucidate the interactions of the MR, LXR, and GR at the transcriptional and functional levels to devise selective targeting of therapeutic agents.
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