Tolvaptan, a selective V2 receptor antagonist (aquaporin), is used in SIADH and autosomal dominant polycystic kidney disease (ADPKD). In ADPKD, tolvaptan slows cyst growth by which mechanism beyond simple aquaresis?

• A Inhibiting mTORC1 signalling in cystic epithelium, reducing cyst cell protein synthesis
• B Reducing renin-angiotensin-aldosterone activation in cystic kidney by decreasing tubular flow
• C Selectively reducing aquaporin-2 expression on principal cells, reducing cyst fluid entry
• D Blocking V2 receptor-mediated cAMP elevation in renal tubular epithelium, which is the primary driver of cyst cell proliferation and fluid secretion in ADPKD ✓

Explanation

In ADPKD, the underlying PKD1/PKD2 mutations result in elevated intracellular cAMP in cystic renal tubular epithelial cells. This cAMP (generated partly via vasopressin V2 receptor stimulation of Gs-adenylyl cyclase pathway) drives two processes: cell proliferation (via cAMP-PKA activation of MEK-ERK pathway) and fluid secretion into cysts (via CFTR chloride channels). Tolvaptan, by blocking the V2 receptor, reduces vasopressin-stimulated cAMP production in cystic epithelial cells, thus addressing the fundamental cAMP-driven pathophysiology of cyst growth and enlargement. This direct anti-cyst mechanism is independent of its aquaretic effect. mTOR inhibitors are a separate therapeutic strategy but not tolvaptan's mechanism.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.