ADH Effects on Renal Tubules
Antidiuretic hormone (ADH) acts primarily on the collecting ducts of the kidney by binding to V2 receptors on basolateral membranes, triggering insertion of aquaporin-2 (AQP2) water channels into the apical membrane, which dramatically increases water permeability and allows water reabsorption from the tubular lumen into the hypertonic medullary interstitium. 1, 2
Molecular Mechanism of Action
The cascade begins when ADH binds to the vasopressin V2 receptor (V2R) on the basolateral membrane of collecting duct principal cells, initiating a G-protein coupled signaling pathway. 1 This activation leads to:
- Adenylyl cyclase activation and cyclic AMP (cAMP) production 1
- Protein kinase A (PKA) stimulation 1
- Exocytotic insertion of AQP2-containing vesicles into the apical (luminal) membrane 1, 3
The inserted AQP2 channels increase apical membrane water permeability dramatically—from baseline osmotic permeability (Pf) of approximately 6 cm/sec to 186 cm/sec with ADH stimulation. 4
Water Transport Pathway
Water moves through a three-step process across the collecting duct epithelium: 1
- Entry through AQP2 channels in the apical membrane (ADH-regulated) 1, 2
- Transit through the cell cytoplasm 1
- Exit through constitutively expressed AQP3 and AQP4 channels in the basolateral membrane (not ADH-regulated) 1, 3
This allows water to flow from the hypotonic tubular lumen to the hypertonic medullary interstitium, concentrating the urine. 1
Regulation Dynamics
Short-Term Regulation
Withdrawal of ADH triggers endocytotic retrieval of AQP2 from the apical membrane back into intracellular vesicles, rapidly decreasing water permeability. 3 This hormone-induced redistribution between intracellular compartments and the cell membrane provides the basis for rapid, short-term regulation of water permeability. 3
Long-Term Regulation
Beyond acute trafficking, ADH also regulates AQP2 and AQP3 expression levels, providing long-term control of water channel abundance. 3
Clinical Context
In heart failure, ADH is activated as part of the maladaptive neurohormonal response to decreased effective circulating volume, working alongside aldosterone to promote water and sodium retention that perpetuates congestion. 1
Aldosterone and ADH have distinct but complementary mechanisms: 2
- Aldosterone increases sodium reabsorption in the distal tubule and collecting duct, leading to secondary water retention 2
- ADH increases free water reabsorption through AQP2 channels without directly affecting sodium transport 2
Pathophysiology
In congenital nephrogenic diabetes insipidus, mutations in either the V2 receptor or AQP2 genes prevent ADH from exerting its antidiuretic effect, resulting in inability to concentrate urine despite high ADH levels. 1 Affected patients present with polyuria, inappropriately dilute urine (osmolality <200 mOsm/kg H2O), and hypernatremia (serum osmolality >300 mOsm/kg H2O). 1
Vasopressin receptor antagonists (vaptans) block ADH-mediated free water reabsorption and are therapeutically useful in treating hypervolemic hyponatremia by promoting aquaresis (free water excretion without significant sodium loss). 2