What Is a Mineralocorticoid?

Mineralocorticoid is a steroid hormone secreted by spheroid cells of the adrenal cortex. Its main physiological role is to maintain the balance of water and electrolytes in the human body.

Mineralocorticoid is a steroid hormone secreted by spheroid cells of the adrenal cortex. Its main physiological role is to maintain the balance of water and electrolytes in the human body.

Mineralocorticoid I. Introduction

Mineralocorticoid is a steroid hormone secreted by the spheroid cells of the adrenal cortex. Its main physiological role is to maintain the balance of water and electrolytes in the body;

Water in the body is also called body fluid. In adult men, body fluids account for 60% of the total weight, and adult women account for 55%. About 40% of them are distributed in cells, called intracellular fluid, and the rest are extracellular fluids, including plasma, lymph, interstitial fluid, cerebrospinal fluid, thoracic and abdominal fluid, and joint fluid. The human body discharges about 1000-2000 ml of urine daily, and drains about 1000 ml of water through the skin, breathing, and stool, which brings out the waste generated in the body; at the same time, a considerable amount of water should be taken to supplement it. It can be said that almost all life activities in the human body are carried out in water, and metabolism is carried out through water. Therefore, it is of great significance to maintain the balance of body fluid volume and the exchange of intracellular and external fluids.

Mineralocorticoids 2. Physiological effects

Water in nature is not pure water, and all contain different amounts of water-soluble substances. The most common are electrolytes, which are positively and negatively charged ions (cations such as hydrogen, potassium, sodium, calcium, magnesium, and anions such as chlorine, phosphorus, and bicarbonate) and some organic substances (proteins, organic acids, etc.), Collectively referred to as solutes. The solutes in the intracellular fluid are mainly potassium ions, while the solutes in the extracellular fluid are mainly sodium and chloride ions.

The main physiological role of mineralocorticoids is to promote renal tubular reabsorption of sodium while retaining water and excretion of potassium. It is coordinated with the antidiuretic hormone secreted by the hypothalamus to maintain the balance of water and electrolytes in the body. Mineralocorticoid's sodium and potassium-retaining effects are also manifested in the salivary glands, sweat glands, and the gastrointestinal tract.

Among natural corticosteroids, aldosterone is the most powerful mineralocorticoid. Its physiological salt effect is 500 times of the equivalent glucocorticoid (cortisol). Under normal physiological conditions, due to the large secretion of glucocorticoids, glucocorticoids account for about 45% of the total body salt effect, and aldosterone also bears 45%. Another mineralocorticoid, deoxycorticosteroids Ketones bear 10%. Normally, the daily secretion of aldosterone is very small. If excessive aldosterone secretion is caused by some circumstances, its significant sodium-water retention and potassium excretion effect can cause hypokalemia, tissue edema, and hypertension. If the level of mineralocorticoid secretion is too low, it will lead to symptoms of water and sodium loss and lower blood pressure.

Mineralocorticoid III. Common mineralocorticoids

Aldosterone

(1) Synthesis and metabolism of aldosterone

Aldosterone is a steroid hormone discovered in 1953. It is made from cholesterol through a series of enzymatic reactions and finally catalyzed by aldosterone synthetase. Aldosterone synthase is encoded by the CYP11B2 gene, which is located on mouse chromosome 15 and human chromosome 8 long arm 8q22. In addition to the adrenal glands, the cardiovascular system and central nervous system also express CYP11B2 enzymes, suggesting that local tissues can synthesize aldosterone and act on corresponding target organs. The metabolism of aldosterone occurs in the liver and is mainly reduced to tetrahydroaldosterone, which is excreted in the urine after combining with glucuronic acid.

(2) the role and regulation of aldosterone

Aldosterone mainly promotes the retention of sodium and potassium by the kidneys to maintain water and salt balance. Its other important role is to regulate the function of target organs by combining with the MR of local tissues in an autocrine or paracrine manner. Aldosterone can regulate the expression of different target genes and protein translation through genomic effects, that is, binding to intracellular receptors, or through rapid non-genomic effects, that is, independent of intracellular receptors and the process of transcription and translation. Not blocked by aldosterone receptor antagonists such as spironolactone. At present, there are more and more studies on the non-genomic effects of aldosterone. It has been found that the non-genomic signaling pathway of aldosterone involves cyclic adenosine monophosphate (cAMP), inositol triphosphate (IP3), calcium ion (Ca2 +), and protein kinase C (PKC). , Extracellular signal-regulated kinase (ERK1 / 2), phosphatidylinositol 3-kinase (PI3K), non-receptor tyrosine kinase (c-src), angiotensin II (Ang II), epidermal growth factor receptor ( EGFR), NADPH oxidase / active oxygen (ROS), nitric oxide synthase (NOS), Na + / H + exchange protein (NHE), etc.

2. Deoxycorticosterone (DOC)

DOC is also an important mineralocorticoid, produced by the adrenal glands and acting as a precursor to aldosterone. Studies have now found that DOC is both a potent mineralocorticoid and a glucocorticoid. DOC is catalyzed by progesterone by 21-hydroxylase, and its secretion rate is about the same as that of aldosterone. Adrenocorticotropic hormone, Ang and K + can affect its secretion. DOC is metabolized in the liver, reduced to tetrahydrodeoxycorticosterone, combined with glucuronic acid, and excreted into the urine. DOC has almost no biological effect at physiological concentrations. When DOC is secreted excessively in the body, it produces a strong mineralocorticoid effect, and similar aldosterone manifestations such as hypertension and hypokalemia occur. The effect of DOC on hypertension is widely recognized, and this effect has also been used to induce experimental hypertension models ^[1] .

Mineralocorticoid IV, mineralocorticoids and their receptors

Aldosterone is mainly synthesized and secreted by the adrenal cortex globular band, with an average secretion of 100-200 / zg / d and a plasma concentration of 0.1-lnmoI / L. It is mainly excreted in the liver. In addition, heart, blood vessels, and other tissues can also synthesize aldosterone and play an autocrine and / or paracrine form, which may be involved in local pathological and physiological processes, such as fibrosis. The raw material for aldosterone synthesis is cholesterol, which is formed by the catalysis of various cytochrome P450s and short-chain dehydrogenases. The most important rate-limiting enzyme is aldosterone synthase (cYP1B2), which catalyzes the conversion of corticosterone to aldosterone. cYP1B2 is encoded by the cYP1B2 gene in autosome 8q21-22. The transcription of this gene is regulated by angiotensin II and potassium. When the level of angiotensin in the blood increases, it binds to specific type I receptors on the spheroid cells, activates phospholipase c, activates the phosphoinositide pathway, and increases the intracellular calcium ion concentration through calmodulin. And calmodulin kinase activate cAMP response element binding protein, which can be combined with the cAMP response element in the aldosterone synthase gene promoter, thereby promoting gene transcription and protein synthesis of aldosterone synthase, resulting in increased aldosterone secretion. In addition, an increase in blood potassium can also promote extracellular calcium ions into cells, and directly promote aldosterone secretion through the above-mentioned cellular pathway. ACTH's regulation of aldosterone is not obvious under physiological conditions, but it can also activate cAMP response element binding protein through cAMP and protein kinase A under stress to promote aldosterone secretion.

The biological action of aldosterone is mainly mediated by mineralocorticoid receptor (MReraloc · rticoidreceptor, MR). Steroid hormone receptors belong to a large family of nuclear receptors. Similar receptors also include retinoic acid receptors, thyroxine receptors, and vitamin D receptors. Their basic structure is very similar, and they all contain three functional domains, namely the N-terminal domain of activated gene transcription, an intermediate domain that binds to a DNA site, and a c-terminal domain that binds to a ligand.

The structure of the N-terminus varies greatly among different nuclear receptors, with homology of <15%. This region is the main site of receptor phosphorylation and contains a domain related to transcriptional activation, called the activation function 1 region (AF1) or Taul region. The N-terminal domain is also the site where the receptor binds to other transcription factors. The highly conserved DNA-binding region is a major feature of the nuclear receptor family, and its structural composition is now clear. This region consists of 66-68 amino acids and contains 9 conserved cysteines. The first eight cysteines interact with two zinc atoms to form two zinc finger structures. Each structure consists of 12 to 13 amino acids, spaced 15 to 17 amino acids apart. In the first zinc finger structure near the N-terminus, the c-terminal helix at the base contains 3 to 4 important amino acids, called P-boxes, which are mainly involved in the recognition and binding of specific DNA sequences on target genes. The other zinc finger has a lower specificity for binding to DNA, but can increase the affinity of the former for binding to DNA. Its base also contains 5 amino acids, called the D box, which mainly provides the interface for the receptor to bind to other proteins to form two Polymer. The c-terminal ligand binding region is also relatively conserved. It is rich in hydrophobic sequences and consists of 200 to 250 amino acids, forming 11 to 12 helix structures, which can provide specific sites for binding to the ligand. Its c-terminus has a ligand-induced transcriptional activation function called the AFz region. In addition, this domain is also involved in the nuclear localization of the receptor and promotes the formation of homodimers. For steroid hormone receptors, this region is also the site where heat shock proteins bind.

Non-activated MR is mainly located in the cytoplasm and is bound to two molecules of heat shock protein. Once aldosterone binds to MR, it can cause changes in the receptor configuration, remove heat shock proteins, form dimers, and activate nuclear localization signals, so that activated receptor ligand complexes are quickly transferred to the nucleus. Subsequently, the DNA binding region is exposed, and the top of the zinc finger binds to the phosphate group on the target gene, recognizes the specific DNA sequence and tightly binds it, and directly affects gene transcription through RNA polymerase II; or indirectly regulates it by interacting with other transcription factors Gene transcription, which in turn produces a series of aldosterone-inducing proteins, but the exact genes regulated by aldosterone are currently poorly understood. In the first 40 mln of aldosterone action, it is reported that 5% of gene transcription can be affected by it. In addition, some of the effects of aldosterone can also be mediated by the intracellular signaling system, causing changes in intracellular calcium ions, cAMt, and cGMP, and rapidly affecting the function of target cells. Recently, aldosterone membrane binding sites have been found in human monocytes, pig livers and kidneys, and many other sites, with an affinity coefficient of about 0.1 nmol / L, which may mediate the rapid cellular effects of aldosterone. Some people have isolated and cloned the progesterone membrane-bound protein in pig liver microsomes, which may be the first steroid hormone membrane receptor.

Mineralocorticoid V. Related diseases

1. Mineralocorticoid and kidney disease

Mineralocorticoid (Mc) is an important hormone that regulates the body's water and salt metabolism. In humans, this type of hormone is mainly aldosteron (Aldo). At present, these hormones are well known, but their mechanism of action is not fully understood. In recent years, studies have found that aldosterone is closely related to diseases such as hypertension and organ fibrosis, so multi-faceted and multi-level research on aldosterone is still in the ascendant. We now know that not only can abnormalities in aldosterone and its receptors cause certain kidney diseases or hypertension, but also that aldosterone can directly participate in the process of renal fibrosis as an independent pathogenic factor.

2. The role of mineralocorticoids in blood pressure regulation

As the main representative of mineralocorticoids, aldosterone directly participates in the kidneys to regulate water and salt metabolism and maintain blood pressure balance. In addition to the kidney, the skin is also an important organ that regulates water and salt metabolism. Titze et al. [28] found that the increase of sodium in the interstitial skin of the skin can increase the osmotic pressure, activate the mononuclear phagocytic system, increase the number of skin lymphatic vessels, and promote reflux. It regulates extracellular fluid volume and blood pressure balance through the TonEBP / VEGFC signaling pathway in monocyte phagocytic cells. Existing studies have shown that mineralocorticoid receptor expression is also present in the skin, which adds a new direction to the study of the body's water-salt balance mechanism. Mineralocorticoid receptors in the heart, kidney and blood vessels regulate blood pressure through different mechanisms and mediate target organ remodeling

3. The effect of mineralocorticoids on insulin resistance

A large number of research results show that many diseases related to insulin resistance (such as obesity and hypertension) have abnormally elevated aldosterone levels, and mineralocorticoids play an important role in the pathophysiology of insulin resistance. Multiple studies have shown that mineralocorticoid receptor antagonists can improve insulin resistance and insulin sensitivity, which provides a new treatment for preventing insulin resistance complications such as diabetes and cardiovascular disease. However, the use of mineralocorticoid receptor antagonists for the treatment of insulin resistance requires further large-scale clinical trials to support ^[2] .