How the System is Triggered
The foundation for RAAS activation is a decrease in renal perfusion pressure. This occurs during hemorrhage, systemic hypotension, or dehydration caused by severe vomiting, diarrhea, and intense sweating. Another important trigger is a drop 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 synthesize and release renin—a specific proteolytic enzyme—into the bloodstream.
Biochemical Cascade of Conversions
The operation of the RAAS represents a series of sequential proteolytic reactions:
- The initial substrate is angiotensinogen, a protein produced by the liver.
- The enzyme renin hydrolyzes angiotensinogen by cleaving off a peptide fragment. This produces inactive angiotensin I, which consists of 10 amino acids.
- Angiotensin-converting enzyme (ACE), also known as carboxydipeptidyl peptidase, steps in to cleave two amino acids from the C-terminus of angiotensin I.
- The final result is the formation of angiotensin II, an active 8-amino-acid peptide.
Effects of Angiotensin II and the Mechanism of Aldosterone
Ready-to-use angiotensin II exerts its effects through three main mechanisms:
- Vasoconstriction: Potently contracts vascular smooth muscle cells, causing blood pressure to rise.
- Central Effect: Stimulates the thirst center.
- Adrenal Activation: Stimulates the synthesis of the mineralocorticoid aldosterone in the adrenal cortex via the inositol trisphosphate system.
Aldosterone is synthesized through the pathway: Cholesterol $\rightarrow$ Pregnenolone $\rightarrow$ Progesterone $\rightarrow$ Corticosterone $\rightarrow$ Aldosterone. Upon entering target cells of the renal tubules, it binds to an intracellular receptor. This complex acts on nuclear DNA, stimulating the synthesis of:
- Epithelial sodium channel (ENaC) components: Inserted into the apical membrane to enhance $Na^+$ reabsorption.
- $Na^+,K^+$-ATPase: Located on the basolateral membrane to pump reabsorbed sodium into the blood.
- TCA cycle enzymes (e.g., citrate synthase): Provide ATP production for active transport.
Sodium retention serves as a signal for hypothalamic osmoreceptors. In response, the secretion of antidiuretic hormone (ADH) from the posterior pituitary nerve terminals is stimulated. ADH enhances water reabsorption in the collecting ducts, ultimately fully restoring blood volume.
Pathophysiology of the RAAS
Malfunctions in the regulatory system lead to severe pathologies:
- Renovascular hypertension: Develops due to localized decreases in perfusion pressure (e.g., from renal artery stenosis or nephrosclerosis). The kidney "erroneously" detects hypotension despite normal systemic pressure and activates the entire RAAS. The result is a persistent, pathological increase in blood pressure. Treatment involves renal revascularization/nephrectomy or ACE inhibitor therapy.
- Primary hyperaldosteronism (Conn syndrome): Arises from an adrenal adenoma or diffuse hyperplasia of the zona glomerulosa cells. Excess aldosterone causes hypernatremia, edema, and hypertension. Concurrently, excessive urinary excretion of $K^+$, $Mg^{2+}$, and protons ($H^+$) leads to muscle weakness and metabolic alkalosis.
- Secondary hyperaldosteronism: Caused by elevated levels of renin and angiotensin II that excessively stimulate the adrenal cortex.