Lysine acetylation of aquaporin-3 does not improve lithium-induced nephrogenic diabetes insipidus.

Abstract

Aquaporin-3 (AQP3) is expressed in the basolateral membrane of the renal principal cell contributing to vasopressin-mediated water reabsorption and urine concentration. We reported that post-translational acetylation of lysine 282 of AQP3 promotes water permeability. In this study, we hypothesized that AQP3 acetylation may improve polyuria in a mouse model of lithium-induced nephrogenic diabetes insipidus (Li-NDI). Wild type, AQP3 acetylation (K282Q), and deacetylation (K282R) mimetic mice were fed a lithium-containing diet or a control diet for 14 days. Body masses and spot urines were collected overtime, while urine flow and osmolality, plasma osmolality and kidneys were collected on day 14 of the diets. All Li-NDI mice had greater urine output and water intake compared to control fed mice and unexpectedly, this was exacerbated in female Li-NDI AQP3-acetylation and AQP3-deacetylation mice. After 14 days of lithium diet, acetylated AQP3 was almost undetectable in the kidneys of WT mice, and AQP3 localization in acetylated and deacetylated mice was minimal. In the setting of LI-NDI, the significant loss of AQP3 was not prevented in acetylated-AQP3 mice and in female mice mutation of K282 resulted in a worsened Li-NDI phenotype suggesting this lysine is critical for promoting sex-specific AQP3-water permeability.