Previous studies demonstrated that ROS-NLRP3 inflammasome signaling activation were involved in the pathogenesis of diabetic nephropathy (DN). But the mechanism by which high glucose prime ROS-NLRP3 inflammasome signaling remains debatable. Recent research has shown that taste receptor type 1, member 2 (T1R2) and member 3 (T1R3), form heterodimers to act as sweet taste receptors (STRs), are widely expressed in the extraoral tissues, and emerging evidence suggests that STRs are important sentinels of innate immunity. As a natural ligand for STRs, whether high glucose prime ROS-NLRP3 inflammasome signaling via STRs is unclear. Therefore, diabetes mellitus (DM) mouse model was induced by streptozotocin (STZ) in vivo, mouse glomerular mesangial cells (GMCs) and human proximal tubular cells were stimulated by elevated concentrations of high glucose (10, 20, and 30 mmol/L) or mannitol as the osmotic pressure (OP) control in vitro, STRs inhibitor lactisole were used as an intervention reagent to evaluated the role and mechanism of the STRs in the pathogenesis of DN. Our results showed that the expression of STRs (T1R2 and T1R3) and associated signalling components (Gα-gustducin, PLCβ2, TRPM5) were obviously down-regulated under the condition of diabetes in vivo and in vitro. Further more, lactisole signifcantly mitigated the production of intracellular ROS and reversed the decrease of Ca2+ and the activation of NLRP3 inflammasome signaling in GMCs stimulated by high glucose (p<0.05). These combined results support the hypothesis that high glucose induced ROS-NLRP3 inflammasome signaling activation in part via STRs, suggesting that STRs may act as new therapeutic targets of DN.
L. Zhou: None. W. Huang: None. Y. Xu: None. C. Gao: None.