Mechanisms of Hypertension: the Expanding Role of Aldosterone

J Am Soc Nephrol 15: 1993–2001, 2004 Mechanisms of Hypertension: The Expanding Role of Aldosterone E. MARIE FREEL and JOHN M.C. CONNELL MRC Blood Pressure Group, Division of Cardiovascular and Medical Sciences, University of Glasgow, Scotland, United Kingdom Abstract. Hypertension is a common disorder that affects a large aldosterone synthase is associated with hypertension, particularly heterogeneous patient population. Subgroups can be identified on in individuals with a high ratio. However, the most consistent the basis of their responses to hormonal and biologic stimuli. association with this variant is a relative impairment of adrenal These subgroups include low-renin hypertensives and nonmodu- 11␤-hydroxylation. This review explores the evidence for this and lators. Aldosterone, the principal human mineralocorticoid, is provides a hypothesis linking impaired 11␤-hydroxylation and increasingly recognized as playing a significant role in cardiovas- hypertension with a raised aldosterone to renin ratio. It is also cular morbidity, and its role in hypertension has recently been speculated that there is substantial overlap between this group of reevaluated with studies that suggest that increased aldosterone patients and previously identified low-renin hypertensives and biosynthesis (as defined by an elevated aldosterone to renin nonmodulators. Thus, these groups may form a neurohormonal ratio) is a key phenotype in up to 15% of individuals with spectrum reflecting different stages of hypertension or indeed hypertension. It was reported previously that a polymorphism form sequential steps in the natural history of hypertension in of the gene (C to T conversion at position Ϫ344) encoding genetically susceptible individuals. High BP remains an important and common clinical problem Aldosterone Biosynthesis and Regulation that affects one in four adults in the United States (1). Histor- Aldosterone, the principal human mineralocorticoid, is pro- ically, hypertension has been subdivided into “essential” and duced in the zona glomerulosa of the adrenal gland. The “secondary” forms. Essential hypertension (cause unknown) hormone is the product of a series of biosynthetic reactions accounts for 95 to 99% of cases and has traditionally been summarized in Figure 1. The final key steps in aldosterone viewed as a consequence of interaction between environmental synthesis are sequential 11-hydroxylation, 18-hydroxylation, and factors (e.g., sodium intake) and genetic background. How- 18-oxidation of the precursor steroid deoxycorticosterone ever, the identity of the genes that predispose to hypertension (DOC) in zona glomerulosa cells. A single enzyme, aldosterone in the great majority of patients remains unknown. A smaller synthase, carries out all of these steps and is encoded by the gene proportion of patients are identified as having secondary hy- CYP11B2. A similar, highly homologous enzyme, 11␤-hydroxy- pertension, as a consequence of some biochemical or mechan- lase (encoded by the gene CYP11B1), acts in parallel in the zona ical pathology that is potentially reversible. More recently, fasciculata to convert 11-deoxycortisol to cortisol. The two genes however, the notion that secondary hypertension is rare has lie in tandem on chromosome 8 in humans and are highly homol- been challenged by the suggestion that primary aldosteronism ogous; the protein products are also very similar and share ~95% (PA; originally thought to be present in only 1% of individuals identity of primary sequence (3). with hypertension) is present in up to 15% of unselected Angiotensin II (Ang II; regulated by the renin-angiotensin individuals with hypertension (2). In this review, we explore system) and plasma potassium are the principal regulators of the concept that altered regulation of aldosterone production is aldosterone production. Ang II stimulates aldosterone secretion a common feature of essential hypertension and PA, with the in response to sodium depletion and reduced extracellular fluid implication that there is substantial overlap between the two. In volume (4), and even small increments in plasma potassium act turn, this could lead to a shift in therapeutic strategies and as a powerful stimulus for aldosterone production (5). Other increased awareness of a role for aldosterone in cardiovascular factors also influence aldosterone production. In particular, pathophysiology. adrenocorticotrophin (ACTH) exerts an acute effect to stimu- late aldosterone production (6), although its importance in long-term regulation of aldosterone is uncertain. Correspondence to Prof. John M.C Connell, MRC Blood Pressure Group, Western Infirmary, Glasgow, G11 6NT, UK. Phone: ϩ44-141-211-2108; Fax: ϩ44-141-211-1763; E-mail: [email protected] Physiologic Actions of Aldosterone 1046-6673/1508-1993 Aldosterone binds to the mineralocorticoid receptor Journal of the American Society of Nephrology (MR), an intracellular receptor that belongs to the steroid/ Copyright © 2004 by the American Society of Nephrology thyroid/retinoid/orphan receptor superfamily (7). Once DOI: 10.1097/01.ASN.0000132473.50966.14 bound, the ligand/receptor complex translocates to the nu- 1994 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 1993–2001, 2004 The gene product(s) resulting from the interaction of aldosterone/MR complexes binding to DNA regulatory elements are termed aldosterone-induced protein(s) (AIP). AIP may have effects on the apical membrane, cellular energy production, and/or the basolateral Na/K-ATPase pump, resulting in increased sodium reabsorption and potassium and hydrogen ion excretion (13) (Figure 2). Recently, a serine/threonine kinase, serum glucocorticoid- regulated kinase (sgk), has been identified as an AIP resulting in an increase in ENaC activity (14). Aldosterone causes phosphorylation and activation of sgk, which in turn increases ENaC activity by an increase in the number of channels at the cell surface (15). The principal ENaC inhibitory accessory protein is Nedd 4 (neuronal precursor cells expressed devel- opmentally downregulated). This ubiquitin protein ligase binds to the C tails of ␤ and ␥ subunits of ENaC, leading to channel Figure 1. Steroid biosynthetic pathway. Synthesis of cortisol and aldo- internalization and degradation. Recent work suggests that the sterone begins with the conversion of cholesterol to pregnenolone by the stimulatory action of sgk on ENaC is mediated through phos- cytochrome p450 side-chain cleavage enzyme located on the inner mi- tochondrial membrane. Sequential dehydrogenation and hydroxylation phorylation of serine residues on Nedd4. Such phosphorylation reactions form deoxycorticosterone (DOC). In the zona fasciculata, not reduces the interaction between Nedd4 and ENaC, leading to all progesterone undergoes 17␣ hydroxylation, and so both DOC and the elevated ENaC cell surface expression (16). cortisol precursor 11-deoxycortisol are formed. In humans, both the zona It is likely that aldosterone affects BP regulation by mech- glomerulosa and zona fasciculata can convert DOC to corticosterone. anisms other than or in addition to simple plasma volume However, formation of aldosterone from DOC through corticosterone is expansion and the associated increase in cardiac output as a unique to the cells of the zona glomerulosa as a result of selective result of its action on sodium homeostasis. For example, acti- a expression of the enzyme aldosterone synthase. 17␣OH ϭ 17 alpha vation of MR in vascular smooth muscle results in alteration in b ␤ ϭ Hydroxylase; 3 HSD Hydroxysteroid dehydrogenase. pressor responsiveness to adrenergic stimulation. Moreover, evidence suggests that aldosterone binding by the MR in cardiac tissue regulates collagen formation (17). It is feasible that cleus and acts as a transcription factor by direct interaction similar action in peripheral blood vessels might result in re- with DNA regulatory elements (the classical genomic effect modeling, which could sustain an elevated BP. This is sup- of aldosterone) (8). As the MR has similar affinities for ported by evidence suggesting that aldosterone levels are in- aldosterone and cortisol, the 11␤-hydroxysteroid dehydro- versely related to arterial compliance in essential hypertension. genase system acts as a gatekeeper to prevent activation by much higher available levels of cortisol (9). The type 2 isoform of this enzyme is found in the renal distal nephron and converts cortisol to its inactive metabolite, cortisone, which has no affinity for the MR. Traditionally, the principal target organ for aldosterone was said to be the kidney; MR are found in high concentration in the renal distal nephron as well as other epithelial sites, such as the colon and ducts of sweat and salivary glands (10). How- ever, MR have also been identified in nonepithelial sites, such as heart, brain, vascular smooth muscle, liver, and peripheral blood leukocytes (10). The best-characterized physiologic effect of aldosterone is to increase the reabsorption of sodium in the kidney and at other secretory epithelial sites at the expense of potassium and hydrogen ions (4). The major sites of aldosterone-induced sodium and potassium transport are luminal cells of the cortical collecting tubules and the distal convoluted tubule. The apically located epithelial sodium channel (ENaC) is the major deter- minant of renal sodium reabsorption (11). Its availability in Figure 2. Intracellular effects of aldosterone on distal collecting open conformation at

Load more