Part Ⅰ：The Pathology Of Aldosterone Biosynthesis And Its Action
Apr 14, 2023
Abstract
Aldosterone plays a key role in the renin-angiotensin-aldosterone system to maintain fluid volume and electrolyte metabolism homeostasis. The action of aldosterone is mediated by the mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Its excessive action can cause tissue damage in target organs, such as myocardial and vascular fibrosis, in addition to chronic kidney disease, directly. Excessive aldosterone action has also been reported to be associated with the imbalance of electrolyte metabolism in inflammatory bowel disease and the development of pulmonary disease. Aldosteronism is initially classified as primary and secondary. Primary aldosteronism is more common and is known to lead to secondary hypertension and subsequent cardiovascular damage. Primary aldosteronism is also divided into different subtypes, with aldosterone-producing adenomas being the most common and accounting for the majority of unilateral primary aldosteronism. Bilateral aldosteronism is dominated by diffuse aldosterone-producing hyperplasia and small aldosterone-producing nodules or nodules as the main subtypes. All of these aldosterone-producing lesions have been reported to have somatic mutations including KCNJ5, CACNA1D, ATP1A1, and ATP2B3, all of which are associated with excessive aldosterone production. Among the above mutations, somatic mutations in KCNJ5 are most common in aldosterone-producing adenomas and are mostly composed of clear cells with abundant expression of aldosterone synthase. In contrast, cacna1d mutations in aldosterone-producing nodules or aldosterone-producing nodules are frequently found not only in patients with primary hyperaldosteronism but also in the glomerular region of normal adrenal glands, which may eventually lead to autonomous aldosterone production resulting in normal or apparent primary hyperaldosteronism, but the details of which remain unclear.
Keywords
aldosterone; 11β-hydroxysteroid dehydrogenase; mineralocorticoid receptor; pathology; primary aldosteronism; Cistanche extract.
Click here to buy Cistanche supplements
Introduction
Aldosterone is a key component of the renin-angiotensin-aldosterone system (RAAS), maintaining homeostasis of fluid volume and electrolyte metabolism (Laragh et al. 1972, Laragh and Sealey 2011, Patel et al. 2017), and is produced in the adrenal glomerular zone (ZG) of the cortex. Aldosterone can bind to the mineralocorticoid receptor (MR) and regulate water, sodium, and potassium reabsorption (Booth et al. 2002; Nakamura et al. 2016; Seccia et al. 2018). However, MR can be activated not only by mineralocorticoids such as aldosterone but also by glucocorticoids, including cortisol and corticosterone, because they have similar binding affinity to MR (Krozowski and Funder 1983; Arriza et al. 1987; Sheppard and Funder 1987). Thus, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) plays a key role in conferring mineralocorticoid specificity through in situ degradation of cortisol or conversion of cortisol to cortisone, and this enzyme has little binding affinity for MR and, as reported by our group, co-localizes with MR in almost all human tissues (Edwards et al. 1988; Funder et al. 1988; Hirasawa et al. 1997,1999,2000; Stewart et al. 1987; Suzuki et al. 1998; Takahashi et al. 1998). In addition, aldosterone has been reported to affect the function of many organs other than the kidney, including cardiac tissue, vascular smooth muscle, colon, lacrimal glands, sweat glands, and bronchial epithelium, and to have deleterious or compensatory effects on the aforementioned organs.
Autonomous overproduction of aldosterone or primary aldosteronism (PA) is commonly associated with somatic mutations in genes including potassium internal rectifier channel subfamily J member 5 (KCNJ5), calcium voltage-gated channel subunit α 1D (CACNA1D), ATPase Na+ /K+ transport subunit α 1 (ATP1A1), and ATPase plasma membrane Ca2+ transport 3 (ATP2B3) are related (Zennaro et al., 2017). Furthermore, these somatic mutations are frequently detected in unilateral or bilateral aldosterone-producing adenomas (APA), aldosterone-producing microspheres (APM), and aldosterone-producing nodules (APN), all of which may result in normal blood pressure or clinically significant PA, although their details remain unknown. Therefore, it is crucial to highlight the following points at this juncture; 1. aldosterone acts in a wide variety of tissues and plays a key role in their pathology; and 2. PA is a common condition that must be detected and treated at an early clinical stage to avoid its immediate and recalcitrant organ damage. Therefore, this article provides a review of the pathophysiology of aldosterone biosynthesis and its role as well as the pathology of PA.
The physiological role of aldosterone in the renin-angiotensin-aldosterone system (RAAS)
RAAS plays a key role in the regulation of extracellular volume, sodium-potassium balance, and vascular system tone in the human physiological state. The first step in RAAS is the synthesis of angiotensinogen in the liver. Angiotensinogen is subsequently converted to angiotensin (Ang) I by activation of renin, which is regulated by renal pressure receptors and sodium chloride (NaCl) transport in the glomerular paracellular apparatus to the dense macula. Thus, alterations in blood pressure and electrolyte balance may lead to elevated renin production, further catalyzing the conversion of angiotensinogen to Ang I as a rate-limiting step in the system. Ang I is subsequently converted to Ang II via angiotensin-converting enzyme (ACE), and ACE is widely released from endothelial cells or other cells. ACE-2 has been reported to convert Ang II to another isoform of the RAAS peptide Ang-(1- 7), which attenuates Ang II and is thought to be a degradation product of Ang II. Ang II binds to the angiotensin II type 1 receptor (AT1R) in the adrenocortical ZG, which subsequently leads to the facilitation of aldosterone biosynthesis.AT2R is thought to be another isoform that antagonizes AT1R to lower blood pressure. Thus, AT1R-stimulated aldosterone elevation is the ultimate dominant factor in RAAS, contributing to the systemic regulation of sodium and fluid volume, as well as renal potassium excretion. Aldosterone also binds to the mineralocorticoid receptor (MR) and increases the activity of tubulointerstitial Na+ channels (ENaC), tubulointerstitial K+ channels, and plasma membrane Na+ /K+ -ATPase. In addition, water follows the cross-cellular movement of Na+ and maintains the balance of body fluid volume.
Herba Cistanche
Aldosterone biosynthesis in the adrenocortical ZG
In adrenocortical ZG, Ang II binding to AT1R is followed by the production of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) following inositol-specific phospholipase C (PLC) activation. Activated IP3 leads to a transient increase in intracellular calcium levels, which in turn activates calcium/calmodulin-dependent protein kinase (CaMK) and ultimately promotes the expression of aldosterone biosynthesis in normal adrenal ZG by activating cAMP response element binding (CREB). Both of these factors increase cytoplasmic Ca and DAG activation of protein kinase C (PKC), which acts on protein kinase D (PKD) to activate CREB to stimulate steroidogenic acute regulatory protein (StAR) transcription, which in turn increases CYP11B2 expression levels (Figure 1).
Like other corticosteroids, cholesterol is a precursor to aldosterone and is subsequently converted to pregnenolone (CYP11A1) upon activation by cytochrome P450 side chain cleavage. Pregnenolone is then converted to progesterone by 3β-hydroxysteroid dehydrogenase (3β- HSD). 21-hydroxylase (CYP21A2) catalyzes the conversion of progesterone to deoxycorticosterone and aldosterone synthase (CYP11B2) finally catalyzes its conversion to aldosterone. On the other hand, cortisol is produced in the zona fasciculate (ZF) through a cascade of various hormone-producing enzymes stimulated by adrenocorticotropic hormone (ACTH). The enzymes involved in the conversion of cholesterol to 11-deoxycortisol include CYP11A1, 17- α -hydroxylase/17,20 lyase (CYP17A1), and HSD3B. Cortisol is ultimately biosynthesized under the activation of 11β-hydroxylase (CYP11B1) (Figure 1).
Normal adrenal gland lesions producing aldosterone
We recently demonstrated that in the vast majority of normal human adrenals, aldosterone is not necessarily produced diffusely, but rather in the ZG in the form of aldosterone-producing micronodules (APMs), formerly known as aldosterone-producing cell clusters (APCCs).APMs are defined as CYP11B2-positive ZG cells under the adrenal envelope, which are usually less than 10 mm in maximum diameter and can only be identified by Neither CYP11B1 nor CYP17A1 immunoreactivity present in these APMs. In contrast to CYP11B2 described above, key steroidogenic enzymes including CYP17A1 and CYP11B1 are widely expressed in the normal zona fasciculata (ZF). Furthermore, we recently reported that the number of APMs in normal ZG increases with age. However, as the number of APMs increased, the total number of CYP11B2-positive regions in APMs also showed a significant negative correlation with age. Taken together, these results suggest that RAAS-independent APMs with more autonomous and less physiological aldosterone production are thought to be associated with aging, whereas focal or localized nodal aldosterone production in the ZG can also be thought to represent aging changes in the adrenal cortex. We will discuss these issues later in this paper.
Standardized Cistanche
11β-Hydroxysteroid Dehydrogenase Type 2 (11β-HSD2)
11β-HSD mediated aldosterone actions in human tissues
As mentioned above, aldosterone acts by binding to MR in the kidney, colon, salivary glands, and other organs. However, the results of early in vitro studies do suggest that MR also has the same affinity for glucocorticoids (e.g., cortisol and corticosterone). Therefore, it is tempting to speculate that under physiological conditions where serum cortisol is much higher than aldosterone, MR can be continuously occupied by cortisol and aldosterone-specific effects are unlikely to occur in humans. However, subsequently reported findings show that MR is selectively activated by picomolar levels of aldosterone in the distal renal unit in vivo, but not by higher nanomolar levels of cortisol. Thus, the differences in the binding affinity of aldosterone and cortisol for MR in vivo and in vitro studies provide interesting but puzzling questions about the mechanism of action of aldosterone. A number of interesting hypotheses have been proposed historically to explain the large discrepancy between the above-mentioned in vitro and in vivo findings. For example, aldosterone has been proposed to cross cell membranes in a more specific manner than cortisol, or some unknown mechanism may exist to alter the intracellular concentrations of both hormones (aldosterone and cortisol). This rather mysterious discrepancy was finally resolved by detailed clinical studies of rare diseases. The lack of conversion from cortisol to cortisone has been reported in the clinical literature. This rare genetic disorder, also known as apparent mineralocorticoid excess syndrome, was reported in children who exhibited marked hypertension, sodium retention, potassium loss, and suppression of plasma renin activity despite undetectable mineralocorticoid levels. The subsequent analysis did reveal that cortisol itself acts as a mineralocorticoid in these patients. Subsequently, it was reported that dexamethasone inhibition of endogenous cortisol reversed various symptoms due to mineralocorticoid overdose, and these symptoms recovered even after the termination of dexamethasone treatment. the mysterious mechanism of this rare but unique genetic disorder was finally clarified in the late 1980s by studying the activity of 11β-hydroxysteroid dehydrogenase (11β-HSD) and the status of this enzyme, MR unbound affinity in various aldosterone target tissues defines aldosterone specificity in vivo. In the kidney, 11β-HSD catalyzes cortisol and corticosterone to cortisone and 11β-dehydrocortisone, respectively, both of which have no binding capacity to MR. Only aldosterone, which is not catalyzed by 11β-HSD, can bind MR and ultimately produce hormone specificity in target tissues in vivo.
The isozyme of 11β-HSD: type 1 and type 2
However, with the discovery of a potential role for the 11β-HSD enzyme in mineralocorticoid action, some conflicting or inconsistent findings have also been reported. For example, 11β-HSD is commonly expressed in the liver, but the liver itself does not have MR in either cell type. in addition, 11β-HSD does not necessarily co-localize with MR in the distal renal unit. The above results suggest that 11β-HSD may exist as an isozyme. Follow-up studies also revealed the existence of a new isozyme or isoform called 11βhsd type 2 (11β- HSD2) in addition to the original form, 11βhsd type 1 (11β-HSD1). 11β-HSD2 can metabolize cortisol to cortisone and can never compete with Mr. binding to aldosterone and above 11β- HSD1 can inactivate the conversion of cortisol to active cortisol. 11β- HSD1 is widely distributed in human tissues, such as the liver, vascular system, adipose tissue, ovaries, testes, and brain. Subsequently, we used dual immunohistochemistry and/or immunohistochemical analysis using a series of mirror tissue sections to demonstrate that 11β-HSD2 co-localizes specifically with MR in almost all aldosterone target tissues, including kidney, heart tissue, vascular smooth muscle, colon, lacrimal gland, sweat gland, bronchial epithelium, and other tissues. We subsequently demonstrated that 11β-HSD2 plays a key role not only in the physiological and pathophysiological actions of aldosterone in these human organs. In the next sections, we will further discuss the pathophysiological role of this very interesting local regulation of aldosterone.
the effects of Cistanche benefits
The Pathology of Aldosterone Actions
Aldosterone Actions in inflammatory bowel disease
Aldosterone can regulate Na+ reabsorption by binding to MR in colonic epithelial cells. In addition, inflammatory bowel disease (IBD) including ulcerative colitis or Crohn's disease has been reported to be accompanied by impaired epithelial Na+ absorption. Ulcerative colitis is characterized by an inflammatory disease of the superficial mucosa from the rectum to the colon, although many exceptions have been reported in a persistent manner. On the other hand, Crohn's disease is defined as transmural inflammation that can affect any part of the gastrointestinal tract from the mouth to the anus, not necessarily in a continuous manner). The above findings suggest that aldosterone may be involved in IBD, especially in relation to clinically severe diarrhea, considering the importance of aldosterone in the regulation of gastrointestinal tract function. We confirmed the expression of 11β-HSD2 in the normal colonic mucosa, ulcerative colitis, and Crohn's disease. In normal colonic mucosa, a clear gradient of 11β-HSD2 expression was detected in the colonic epithelium and colonic crypt, i.e., more pronounced diffusion to the mucosal surface. However, 11β-HSD2 was reduced or even absent in surface epithelial cells surrounding severe ulcerative lesions in ulcerative colitis. In addition, both protein and mRNA levels of 11β-HSD2 were not expressed or were reduced in ulcerative colitis compared with colonic epithelial cells adjacent to uninflamed mucosa. Of particular importance, there was also no significant difference in 11β-HSD2 expression between patients with ulcerative colitis who received preoperative corticosteroids and those who did not. This interesting finding suggests that glucocorticoid treatment of patients with ulcerative colitis has little effect on the expression of 11β-HSD2 in colonic epithelial cells. The reduction of 11β-HSD2 expression in ulcerative colitis has also been reported to be mediated by pro-inflammatory cytokines, including tumor necrosis factor (TNF)- α and interleukin (IL)-1, through in vitro studies and mouse models. In summary, ulcerative colitis inflammatory cells can mediate the expression of 11β-HSD2 through both transcriptional and translational pathways, leading to abnormal absorption of water and Na+ in patients, resulting in clinically significant diarrhea. The above findings shed new light on the pathophysiology of patients with ulcerative colitis.
