SGLT2 gene expression in thirst-promoting NOS1 neurons and vasopressin-synthesizing neurons in male rats.

While sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects, they cause only mild changes in body fluid balance, partly through compensatory increases in water intake and vasopressin (AVP) secretion. However, whether SGLT2 inhibitors directly influence central pathways governing these fluid-regulatory responses remains unclear. We here investigated Sglt2 expression in thirst-regulating centers, the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO) and hypothalamic AVP-synthesizing regions, including the supraoptic nucleus (SON) and paraventricular nucleus (PVN). Droplet digital PCR analysis revealed Sglt2 expression in all regions, at levels comparable to angiotensin receptor 1a, a key regulator of drinking behavior. In situ hybridization confirmed Sglt2 mRNA signals in OVLT, SFO, SON, and PVN. Double in situ hybridization revealed that Sglt2 is co-expressed in approximately 48%-60% of thirst-promoting NOS1 neurons in the OVLT and SFO. Furthermore, Sglt2 was detected in over 80% of AVP-synthesizing neurons and approximately 60% of oxytocin neurons within the SON and PVN. Our findings suggest that SGLT2 inhibitors have the potential to directly modulate central thirst and neuroendocrine responses, offering a novel anatomical framework for understanding their systemic effects on fluid balance and cardio-renal protection.