How the system is activated
The foundation for RAAS activation is a decrease in renal perfusion pressure. This occurs during blood loss, a general drop in blood pressure, or dehydration due to severe vomiting, diarrhea, and intense sweating. Another important trigger is a decrease in $NaCl$ concentration.
Juxtaglomerular cells located in the afferent arterioles of the kidneys respond to these changes. When blood pressure drops or baroreceptor signaling decreases, they begin to synthesize and release renin—a specific proteolytic enzyme—into the bloodstream.
Biochemical cascade of transformations
The function of the RAAS is a series of sequential proteolytic reactions:
- The initial substrate is angiotensinogen, a protein produced by the liver.
- The enzyme renin hydrolyzes angiotensinogen, cleaving off a peptide fragment. This results in the formation of inactive angiotensin I, which consists of 10 amino acids.
- Angiotensin-converting enzyme (ACE), also known as carboxydipeptidyl peptidase, comes into play. It cleaves two amino acids from the C-terminus of angiotensin I.
- The result is the formation of angiotensin II, an active peptide consisting of 8 amino acids.
Effects of Angiotensin II and the mechanism of aldosterone
The resulting angiotensin II exerts its effects through three mechanisms:
- Vasoconstriction: powerfully contracts vascular smooth muscle cells, causing blood pressure to rise.
- Central effect: stimulates the thirst center.
- Adrenal activation: via the inositol trisphosphate system, it stimulates the synthesis of the mineralocorticoid aldosterone in the adrenal cortex.
Aldosterone is synthesized via the pathway: Cholesterol $\rightarrow$ Pregnenolone $\rightarrow$ Progesterone $\rightarrow$ Corticosterone $\rightarrow$ Aldosterone. Upon entering target cells in the renal tubules, it binds to an intracellular receptor. This complex acts on nuclear DNA, stimulating the synthesis of proteins:
- Sodium channel components (ENaC): insert into the apical membrane, enhancing $Na^+$ reabsorption.
- $Na^+,K^+$-ATPase: localizes to the basolateral membrane, pumping reabsorbed sodium into the blood.
- TCA cycle enzymes (e.g., citrate synthase): ensure ATP production for active transport.
Sodium retention serves as a signal for hypothalamic osmoreceptors. In response, the secretion of antidiuretic hormone (ADH) from the nerve terminals of the posterior pituitary is stimulated. ADH enhances water reabsorption in the collecting ducts, which ultimately restores blood volume.
Pathophysiology of the RAAS
Faults in the regulatory system lead to the development of severe pathologies:
- Vasorenal (renal) hypertension: develops during a localized drop in perfusion pressure (e.g., due to renal artery stenosis or nephrosclerosis). The kidney "erroneously" detects hypotension against the background of normal systemic pressure and activates the entire RAAS. The result is a persistent rise in blood pressure above normal. It is treated by nephrectomy or the administration of ACE inhibitors.
- Primary hyperaldosteronism (Conn's syndrome): occurs due to an adrenal adenoma or diffuse hypertrophy of the zona glomerulosa cells. Excess aldosterone causes hypernatremia, edema, and hypertension. At the same time, $K^+$, $Mg^{2+}$, and protons ($H^+$) are excessively excreted, leading to muscle weakness and metabolic alkalosis.
- Secondary hyperaldosteronism: caused by elevated levels of renin and angiotensin II, which excessively stimulate the adrenal cortex.
Briefly: answers to topical questions
In the vascular endothelium of which organs is the activity of angiotensin-converting enzyme (ACE) the highest?
The highest activity and primary localization of angiotensin-converting enzyme (ACE) is in the lungs. Sources indicate that ACE is produced mainly in the lungs and is also present in the vascular endothelium of other organs.
In the RAAS cascade, ACE, or carboxydipeptidyl peptidase, converts angiotensin I into angiotensin II by cleaving a dipeptide / two amino acids from the C-terminus.
What types of receptors does angiotensin II bind to in order to produce vasoconstriction?
Angiotensin II interacts with two types of membrane receptors on target cells: AT1 and AT2.
Sources also indicate that angiotensin II is a potent vasoconstrictor: it causes blood vessel constriction, contraction of vascular smooth muscle cells, and an increase in blood pressure.
What stimuli, besides angiotensin II, can directly trigger the secretion of aldosterone by the adrenal cortex?
In addition to angiotensin II, aldosterone secretion by the adrenal cortex is directly stimulated by an increase in blood potassium concentration.
By negative feedback, the regulation of this mineralocorticoid's secretion occurs as follows:
- Hyperkalemia — stimulates hormone secretion.
- Hypokalemia — inhibits secretion.
The released aldosterone enhances the excretion of potassium ions and protons, while also stimulating the reabsorption of sodium ions in the distal convoluted tubules, restoring the normal electrolyte balance in body fluids.
Cascade: Renin Cleaves angiotensinogen (to 10 aa), ACE Actively cleaves (to 8 aa), Aldosterone Accumulates sodium.
Class and exam questions
How do ACE inhibitors work in renal hypertension?
The drugs block the enzyme ACE, interrupting the conversion of inactive angiotensin I into active angiotensin II. This reduces vasoconstriction and aldosterone production, decreasing water and sodium retention, which leads to a drop in blood pressure.
How to distinguish primary hyperaldosteronism from secondary?
Differential diagnosis is based on measuring plasma renin activity. In primary hyperaldosteronism (Conn's syndrome), renin activity is decreased due to negative feedback. In secondary hyperaldosteronism, renin activity is increased.
Why does metabolic alkalosis develop in Conn's syndrome?
Excess aldosterone causes the kidneys not only to reabsorb sodium but also to excessively excrete potassium ions and protons ($H^+$) into the urine. The loss of acid equivalents ($H^+$) shifts blood pH toward the alkaline side, resulting in metabolic alkalosis.
What else to study on this topic
- The mechanism of intracellular signal transduction via the inositol trisphosphate system
- Synthesis of channel proteins (ENaC) and TCA cycle enzymes under the action of aldosterone
- The connection between the RAAS and the secretion of antidiuretic hormone (ADH)
- The negative feedback principle in renin regulation
- Differential diagnosis of Conn's syndrome and secondary hyperaldosteronism
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