Advisory Committee Chair
Kelly Hyndman
Advisory Committee Members
Adam Wende
David Pollock
Malgorzata Kasztan
Mark Bevensee
Document Type
Dissertation
Date of Award
1-1-2025
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Aquaporin-3 (AQP3) mediates basolateral water transport in the kidney collecting duct principal cells, contributing to vasopressin-mediated urine concentration. We previously identified a novel post-translational modification of AQP3, the acetylation of lysine 282 (K282), which we hypothesized as a positive regulator of AQP3 water permeability. First, we found that collecting duct K282 acetylated AQP3 increased upon water deprivation, suggesting an involvement in renal water balance. To decipher the functional role of this modification, we utilized AQP3 acetylation (K282Q or Q) and deacetylation (K282R or R) mimetic mutant mice models generated using CRISPR/Cas9 knock-in technology. Both male and female wild-type (WT) and mutant mice were used, and mice were evaluated under basal conditions, hydration or water deprivation, or in response to vasopressin 2 receptor (V2R) activation or inhibition. At baseline, the mutations did not affect the kidney transcriptome, AQP3 abundance, nor subcellular localization. Under dehydration, all mice excreted a concentrated urine; however, the female Q mutants exhibited significantly greater 24 h urine osmolality than WT, suggesting greater water reabsorption. In response to acute V2R activation by the agonist dDAVP, all mice produced a concentrated urine; however, female Q mutants had a more dilute plasma than WT, further suggesting greater water retention. In support of this finding, Q mutant cells exhibited greater water permeability than WT and R cells in vitro. To determine the potential therapeutical role of AQP3 K282 acetylation, we used a mouse model of lithium-induced nephrogenic diabetes insipidus (NDI), a water balance disorder characterized by compromised response to vasopressin. WT, Q, and R mice were fed a lithium-containing diet for 14 days. Unexpectedly, both Q and R mutant mice exhibited more severe NDI phenotype than WT, suggesting that the K282 residue may be involved in regulatory events independent of lysine acetylation that is important for the urine concentration process in lithium-induced NDI. Collectively, we conclude that AQP3 K282 acetylation promotes renal principal cell water reabsorption, and the effect is more prominent in females during antidiuresis (water deprivation or V2R activation), however, it is not essential for urine concentration. Furthermore, K282 may have other roles that is independent of lysine acetylation.
Recommended Citation
Huynh, Nha Van, "The Role Of Aquaporin-3 Lysine 282 Acetylation In Renal Water Balance" (2025). All ETDs from UAB. 6847.
https://digitalcommons.library.uab.edu/etd-collection/6847
Comments
etdadmin_upload_1142407