GPR39 deletion protects mpkCCD cells from lithium-induced loss of AQP2

Lithium therapy can cause nephrogenic diabetes insipidus (NDI) by reducing aquaporin-2 (AQP2) expression in the renal collecting duct, yet the molecular mediators of this response remain unclear. Previous data from our group and our collaborators (PMID: 40172982) indicates that the activation the G protein-coupled receptor GPR39 promotes diuresis. We hypothesized that the G protein-coupled receptor GPR39 contributes to lithium-induced impairment of water reabsorption, and that loss of GPR39 would protect against lithium-induced downregulation of AQP2. To test this, we used wild-type (WT) and CRISPR-generated GPR39 knockout (KO) mpkCCD cells treated with dDAVP, and, with or without lithium treatment. Lithium treatment consisted of 10 mM lithium on the apical side and 1 mM lithium on the basolateral side for four days with dDAVP-induced AQP2 expression. Western blot densitometry analysis showed that lithium significantly decreased total AQP2 protein in WT cells, consistent with established models of lithium-induced NDI (non-glycosylated AQP2 WT Control: 0.83 ± 0.08 A.U., n=4; WT lithium: 0.44 ± 0.13 A.U., n=4, p=0.03; glycosylated AQP2 WT Control: 1.00 ± 0.08 A.U., n=4; WT lithium: 0.53 ± 0.29 A.U., n=4, p=0.008). In contrast, lithium-treated KO cells maintained AQP2 expression at levels comparable to untreated controls, demonstrating a significant protective effect (non-glycosylated AQP2 KO Control: 0.79 ± 0.27 A.U., n=4; KO lithium: 0.71 ± 0.12 A.U., n=4, p=0.99; glycosylated AQP2 KO Control: 1.15 ± 0.27 A.U., n=4; KO lithium: 0.99 ± 0.07 A.U., n=4, p=0.79). Our findings support a previously unrecognized role for GPR39 in the cellular mechanisms underlying lithium-induced NDI and suggest that inhibition of GPR39 may be a potential therapeutic strategy when treating NDI. Research was supported by the Dean’s ASPIRE undergraduate research grant. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.