Empagliflozin Accelerates Escape from Vasopressin in Rats

Abstract

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) consists of unregulated, elevated vasopressin levels and can lead to hyponatremia. Vasopressin escape is the body’s defense mechanism to limit hyponatremia. The sodium‐glucose transporter (SGLT‐2) inhibitor, empagliflozin, was identified as a treatment for hyponatremia; however, the mechanism of empagliflozin’s effect is unclear. This project investigates empagliflozin’s impact on vasopressin escape in rats with the hypothesis that empagliflozin accelerates escape via key transport protein alteration. Rats were implanted with vasopressin mini‐pumps to mimic SIADH. The first cohort consisted of male rats and a second cohort compared responses in female rats. On day 2, half the rats were given empagliflozin (~15 mg/kg) via diet. Rats were sacrificed on days 7 or 14. Blood and kidney tissue were collected. Total Aquaporin‐2 (AQP2), pSer‐Aquaporin‐2, and NKCC2 were analyzed by western blot. At day 7, serum sodium levels for the female rats were: empagliflozin 110.1+1.7 mmol/L vs 93.3+1.1 mmol/L for the controls (n=5, p<0.001). Serum sodium levels for the male rats were: empagliflozin 136.0+4.8 mmol/L vs 121.4+3.0 mmol/L for the controls (n=4, p<0.05). NKCC2 abundance in the empagliflozin group was 60% lower than control on day 7 (n=5, p<0.05) for female rats, and 77% lower than control in male rats (n =4, p<0.001). Because changes in the AQP2 levels were similar between the sexes, these data were combined. Total AQP2 abundance was 2.3 fold increased in the empagliflozin group on day 7 and 8 fold greater in the empagliflozin group at day 14 (n=9) compared to the control group. Both pSer256‐AQP2 and pSer261‐AQP2 were increased in the empagliflozin groups at both 7 and 14 days vs their respective control groups. pSer256‐AQP2 increased 2.1 (day 7) and 8.5 fold (day 14); pSer261‐AQP2 increased 3.2 fold (day 7) and 5.0 fold (day 14) (n=9/group). We conclude that empagliflozin accelerates vasopressin escape during SIADH primarily through a decrease in NKCC2 abundance in both male and female rats. This will hasten recovery from hyponatremia in SIADH.