MON-539 FKBP5 Links HPA Axis Dysregulation to Elevated Glycosuria in Renal GLUT2 KO Mice: Implications for SGLT2 Inhibitors

Disclosure: M.T. Otunla: None. We recently showed that kidney-specific glucose transporter 2 knockout (Ksp-Glut2 KO) mice exhibit glycosuria and have an overactive hypothalamic-pituitary-adrenal (HPA) axis. This observation suggests a potential crosstalk between elevated glycosuria and stress-related comorbidities, particularly in the context of currently used SGLT2 inhibitors. To investigate the mechanism underlying the HPA axis dysregulation in renal Glut2 KO mice we performed single nucleus RNA sequencing on renal tissue, analyzed their behavior (light/dark box, elevated plus maze, forced swim, open field, and hot plate tests), induced acute and chronic stress using a physical restraint and measured their corticosterone levels. RNA sequencing revealed that the Fkbp5 gene, which has been implicated in contributing to stress-associated psychiatric disorders, diabetes and obesity, was differentially expressed in the renal tissues of Glut2 KO mice. Specifically, it was significantly upregulated in the endothelial cells and downregulated in the proximal tubules of the kidneys. The qPCR analysis showed that the Glut2 KO mice exhibited decreased Fkbp5 expression in the skeletal muscle (100.0±12.19 vs 36.7±5.1, p<0.05) and increased expression in the liver (100.0±20.5 vs 226.7±11.2, p<0.05). This result suggests tissue-specific alterations in glucocorticoid signaling. Moreover, renal Glut2 KO mice had higher levels of plasma corticosterone at baseline (36.6±7.0 vs 48.7±8.7 ng/ml control vs experimental), after acute stress (153.7±18.4 vs 243.3±12.0 ng/ml) and following chronic stress (199.5±9.7 vs 262.0±14.4 ng/ml). The behavioral tests demonstrated that renal Glut2 KO mice had lower frequency of entry into the light side arena (56.5±5.1 vs 46.2±3.0 control vs experimental) along with a reduced mean activity in the Forced Swim Test (0.57±0.19 vs 0.13±0.01, p<0.05), suggesting an impairment in stress-handling capacity. In addition, the KO mice exhibited a lower frequency of entry into the closed arms (13.0±2.0 vs 7.6±1.4, p<0.05) and spent more time in the closed arms (167.0±19.5 vs 236.0±15.2, p<0.05), indicating a preference for the enclosed, safer areas, consistent with increased anxiety-like behavior. The experimental mice also showed reduced motivation or increased depression-like behavior as evidenced by a higher average percentage and a longer cumulative duration of inactivity. Finally, the Glut2 KO mice showed lower latency (10.7±0.9 vs 7.8±0.3, p=0.0114) to react during the hot plate test, indicating their hypersensitivity to pain. In summary, our findings identify Fkbp5 as a critical mediator of HPA axis dysregulation in renal Glut2 KO mice, linking renal glycosuria to stress-associated behaviors. These results have important implications for the use of SGLT2 inhibitors, particularly in individuals with preexisting neurological disorders. Presentation: Monday, July 14, 2025