General characteristics of water and electrolyte balance regulation
The maintenance of water and electrolyte homeostasis is ensured by the coordinated action of several hormones and one integrative system: antidiuretic hormone (ADH), aldosterone, renin-angiotensin-aldosterone system (RAAS), and atrial natriuretic peptide (ANP). The kidneys are the main effector organ, and the key regulatory zone is the distal tubules and collecting ducts, where facultative reabsorption of water and sodium takes place.
Antidiuretic hormone (vasopressin)
ADH is a 9-amino acid peptide with a single disulfide bond. It is synthesized in the neurons of the anterior hypothalamus, transported via axons in a complex with the carrier protein neurophysin to the posterior pituitary, from which it is secreted into the blood. The main stimulus for secretion is an increase in sodium concentration and extracellular fluid osmolality.
ADH has two types of receptors:
- V1 receptors are located in vascular smooth muscle; their activation causes vasoconstriction (hence the hormone's alternative name, vasopressin).
- V2 receptors are localized in the cells of the collecting ducts and are responsible for water balance.
V2 activation occurs via the adenylyl cyclase system: an increase in cAMP concentration activates protein kinase A, which triggers a phosphorylation cascade and the induction of transcription factors for the synthesis of aquaporin-2 (AQP2). AQP2 is inserted into the apical membrane of the cells, ensuring water reabsorption. In the absence of ADH, water reabsorption in this segment does not occur, which forms the basis for the differential diagnosis of diabetes mellitus and diabetes insipidus.
Aldosterone
Aldosterone is a steroid hormone synthesized in the zona glomerulosa cells of the adrenal cortex from cholesterol. Stimuli for synthesis include a decrease in extracellular sodium concentration, an increase in potassium concentration, and activation of the RAAS.
The effects of aldosterone on target cells are mediated through the induction of the synthesis of three groups of proteins:
- Components of the epithelial sodium channels (ENaC) of the apical membrane for Na⁺ entry into the cell.
- Enzymes of the tricarboxylic acid (TCA) cycle to increase ATP production.
- Subunits of the Na⁺/K⁺-ATPase of the basolateral membrane for active transport of Na⁺ out of the cell into the blood and K⁺ into the cell.
The net effect is the retention of NaCl in the body (chlorides follow sodium along an electrochemical gradient) and the excretion of potassium.
Renin-angiotensin-aldosterone system
The RAAS is activated when renal perfusion pressure drops: blood loss, dehydration, renal artery stenosis, nephrosclerosis. A drop in pressure in the afferent glomerular arteriole stimulates the secretion of renin by juxtaglomerular cells.
- Renin is a proteolytic enzyme that cleaves angiotensinogen (a protein synthesized by the liver) to form angiotensin I (10 amino acids).
- Angiotensin-converting enzyme (ACE) is a carboxydipeptidyl peptidase unique in its ability to cleave two amino acids from the C-terminus. This results in the formation of angiotensin II (8 amino acids).
Effects of angiotensin II:
- Powerful vasoconstriction via the inositol phosphate system and an increase in intracellular Ca²⁺ concentration leads to an increase in blood pressure.
- Stimulation of aldosterone secretion in the adrenal zona glomerulosa leads to the retention of Na⁺ and water.
- Mediated stimulation of ADH secretion via increased osmolarity leads to water retention.
- Induction of the sense of thirst leads to increased water intake and circulating blood volume.
Clinical situations of RAAS activation: profuse vomiting, diarrhea, profuse sweating, blood loss — all conditions requiring the restoration of circulating blood volume.
Atrial Natriuretic Peptide
ANP is produced by atrial cardiomyocytes in response to their stretch during elevated blood pressure and circulating blood volume. It acts as a functional antagonist to the RAAS.
Main effects:
- Inhibition of renin secretion — blocks the formation of angiotensin I and II.
- Suppression of aldosterone synthesis — reduces sodium reabsorption.
- Inhibition of ADH secretion — reduces water reabsorption.
- Direct spasmolytic (vasodilatory) action on vascular walls.
The net result is a decrease in circulating blood volume and blood pressure.
Key points
- ADH is synthesized in the hypothalamus, secreted by the posterior pituitary, and enhances water reabsorption in the collecting ducts via V2 receptors and aquaporin-2.
- V1 receptors for ADH mediate vasoconstriction, which explains the hormone's alternative name, vasopressin.
- Aldosterone is a mineralocorticoid of the adrenal zona glomerulosa that induces the synthesis of ENaC, TCA cycle enzymes, and Na⁺/K⁺-ATPase, retaining NaCl and excreting K⁺.
- The trigger for the RAAS is a decrease in renal perfusion pressure; renin initiates the proteolytic cascade of angiotensinogen.
- ACE is a carboxydipeptidyl peptidase that converts angiotensin I into active angiotensin II.
- Angiotensin II causes vasoconstriction and stimulates aldosterone, ADH, and the sensation of thirst, thereby increasing blood pressure.
- ANP is a RAAS antagonist: it suppresses renin, aldosterone, and ADH, and dilates blood vessels, lowering blood pressure.
- Imbalance between the RAAS and ANP underlies water-electrolyte disorders and arterial hypertension.