928-P: The SGLT2 Inhibitor Canagliflozin Ameliorates Polycystic Ovary Syndrome and Attenuates Inflammation by Reducing the Activation of NLRP3 Inflammasome

Polycystic ovary syndrome (PCOS) is closely related to chronic low-grade inflammation and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome. The sodium-glucose cotransporter 2 (SGLT2) inhibitor reduces inflammation and attenuates the progression of PCOS. We assessed whether canagliflozin (CAN) alleviates PCOS by attenuating the NLRP3 inflammasome activation. C57BL/6 mice were treated with dehydroepiandrosterone and a high-fat diet to induce PCOS models for 21 days. Then PCOS mice were randomly divided into two groups: PCOS group and PCOS+CAN group, treated with vehicle or 25mg/kg/day CAN for 21 days by daily oral gavage. In vitro, NLRP3 inflammasome was induced by using lipopolysaccharides (LPS) and adenosine 5'-triphosphate (ATP) in mouse-primary-granulosa-cells (mpGCs), followed by CAN intervention. After CAN intervention, irregular estrous cycle and ovarian morphology with fewer corpora lutea and antral follicles, but more atretic follicles and cysts in PCOS mice were improved. Compared with PCOS group, the levels of testosterone, glucose metabolism, insulin resistance, and triglycerides were improved after the use of CAN. Immunohistochemical staining showed that levels of NLRP3 were down-regulated in the ovarian tissues of PCOS+CAN group compared to PCOS group. The mRNA and protein levels of NLRP3, the inflammasome adapter protein ASC and Caspase-1, N-terminal fragment of gasdermin D (GSDMD-N), downstream inflammatory factors IL-1β and IL-18 in PCOS+CAN group were significantly lower than those in PCOS group. In vitro, LPS+ATP-induced inflammation in mpGCs led to activation of the NLRP3 inflammasome, and this effect was prevented by the addition of CAN. These results showed that canagliflozin attenuated the reproductive and metabolic characteristics of PCOS and ameliorated inflammation by ameliorating activation of the NLRP3 inflammasome.