Osmotic diuresis by SGLT2 inhibition stimulates vasopressin‐induced water reabsorption to maintain body fluid volume

• Published in: Physiological reports Vol. 8; no. 2; pp. e14360 - n/a
• Main Authors: Masuda, Takahiro, Muto, Shigeaki, Fukuda, Keiko, Watanabe, Minami, Ohara, Ken, Koepsell, Hermann, Vallon, Volker, Nagata, Daisuke
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.01.2020; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Aquaporin 1; Aquaporin 2; Aquaporins; bioimpedance analysis; Blood pressure; Body Fluid Compartments - drug effects; Body Fluid Compartments - metabolism; Body Fluids - drug effects; Body Fluids - metabolism; Body weight; Diabetes; Diabetes mellitus; Diuresis; Diuresis - drug effects; Diuresis - physiology; Diuretics; Diuretics, Osmotic - pharmacology; Electrolytes; Fluid intake; Food; Food intake; Glucose transporter; Glucosides - pharmacology; glucosuria; Heart failure; Kidneys; Membrane proteins; Metabolism and Regulation; Na+/glucose cotransporter; Original Research; Osmosis - drug effects; Osmosis - physiology; Physiology; Rats; Reabsorption; Renal function; Renal Physiology; Renal Reabsorption - drug effects; Renal Reabsorption - physiology; Renal tubules; SGLT2 inhibition; Sodium; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Spectroscopy; Thiophenes - pharmacology; Urine; Vasopressin; Vasopressins - urine; Water - metabolism; water reabsorption; Japan; water reabsorption; bioimpedance analysis; SGLT2 inhibition; vasopressin; glucosuria
• ISSN: 2051-817X; 2051-817X
• DOI: 10.14814/phy2.14360

Most of the filtered glucose is reabsorbed in the early proximal tubule by the sodium‐glucose cotransporter SGLT2. The glycosuric effect of the SGLT2 inhibitor ipragliflozin is linked to a diuretic and natriuretic effect that activates compensatory increases in fluid and food intake to stabilize body fluid volume (BFV). However, the compensatory mechanisms that are activated on the level of renal tubules remain unclear. Type 2 diabetic Goto‐Kakizaki (GK) rats were treated with vehicle or 0.01% (in diet) ipragliflozin with free access to fluid and food. After 8 weeks, GK rats were placed in metabolic cages for 24‐hr. Ipragliflozin decreased body weight, serum glucose and systolic blood pressure, and increased fluid and food intake, urinary glucose and Na+ excretion, urine volume, and renal osmolar clearance, as well as urine vasopressin and solute‐free water reabsorption (TcH2O). BFV, measured by bioimpedance spectroscopy, and fluid balance were similar among the two groups. Urine vasopressin in ipragliflozin‐treated rats was negatively and positively associated with fluid balance and TcH2O, respectively. Ipragliflozin increased the renal membrane protein expression of SGLT2, aquaporin (AQP) 2 phosphorylated at Ser269 and vasopressin V2 receptor. The expression of SGLT1, GLUT2, AQP1, and AQP2 was similar between the groups. In conclusion, the SGLT2 inhibitor ipragliflozin induced a sustained glucosuria, diuresis, and natriuresis, with compensatory increases in fluid intake and vasopressin‐induced TcH2O in proportion to the reduced fluid balance to maintain BFV. These results indicate that the osmotic diuresis induced by SGLT2 inhibition stimulates compensatory fluid intake and renal water reabsorption to maintain BFV. We show in this study that SGLT2 inhibitor ipragliflozin induced a sustained glucosuria, diuresis, and natriuresis, with compensatory increases in fluid intake and vasopressin‐induced aquaporin‐2 phosphorylation and solute‐free water reabsorption in proportion to the reduced fluid balance to maintain body fluid volume These results indicate that the osmotic diuresis induced by SGLT2 inhibition stimulates compensatory fluid intake and renal water reabsorption to maintain body fluid volume.