alphaENaC-mediated lithium absorption promotes nephrogenic diabetes insipidus

Area of Science:

• Nephrology
• Molecular Biology
• Physiology

Background:

• Lithium treatment can cause nephrogenic diabetes insipidus (NDI), characterized by polyuria and impaired water reabsorption.
• The amiloride-sensitive epithelial sodium channel (ENaC) is implicated in lithium transport into kidney collecting duct cells.

Purpose of the Study:

• To investigate the role of ENaC in the collecting duct (CD) in the development of lithium-induced NDI.
• To determine if blocking ENaC in the CD can prevent lithium toxicity in the kidneys.

Main Methods:

• Utilized transgenic mice with αENaC specifically knocked out in the collecting duct (CD KO mice) and littermate controls.
• Administered chronic lithium treatment to both KO and control mice.
• Monitored water intake, urine output, urine osmolality, and measured aquaporin 2 (AQP2) and H(+)-ATPase expression.

Main Results:

• CD KO mice showed no significant increase in water intake or polyuria following lithium treatment, unlike control mice.
• Lithium-induced reduction in AQP2 levels was less pronounced in the inner medulla of CD KO mice compared to controls.
• Lithium-induced expression of H(+)-ATPase in the inner medulla was observed in control mice but not in CD KO mice.

Conclusions:

• Absence of functional ENaC in the collecting duct principal cells protects against lithium-induced NDI.
• These findings support the hypothesis that ENaC-mediated lithium entry into collecting duct cells is a key mechanism in the pathogenesis of lithium-induced NDI.