A patient on lithium therapy develops nephrogenic diabetes insipidus. The mechanism is impaired aquaporin-2 (AQP2) insertion in collecting duct principal cells because lithium:

• A Blocks V2 receptors on principal cells, preventing ADH binding
• B Enters principal cells via ENaC and inhibits adenylyl cyclase, reducing cAMP-mediated AQP2 trafficking ✓
• C Competes with Na+ at the luminal Na+/K+-ATPase, reducing the medullary concentration gradient
• D Causes tubular obstruction by precipitating with urinary proteins

Explanation

Lithium enters collecting duct principal cells via the epithelial sodium channel (ENaC) on the luminal side. Intracellularly, lithium inhibits glycogen synthase kinase-3β (GSK-3β) and adenylyl cyclase, reducing intracellular cAMP generation downstream of V2 receptor activation. Without adequate cAMP, protein kinase A is not activated, AQP2 channels are not phosphorylated and trafficked to the apical membrane, and free water reabsorption fails. Because the block is downstream of V2 receptor activation, ADH levels are high but ineffective — classic nephrogenic DI. Amiloride (ENaC blocker) can prevent lithium entry and treat this condition.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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Written and medically reviewed by the StethoPrep medical team.