Responses of renal hemodynamics and tubular functions to acute sodium-glucose cotransporter 2 inhibitor administration in non-diabetic anesthetized rats

Abstract

The aim of this study is to examine the effects of acute administration of luseogliflozin, the sodium-glucose cotransporter 2 (SGLT2) inhibitor, on renal hemodynamics and tubular functions in anesthetized non-diabetic Sprague Dawley (SD) rats and 5/6 nephrectomized (Nx) SD rats. Renal blood flow (RBF), mean arterial pressure (MAP), and heart rate (HR) were continuously measured and urine was collected directly from the left ureter. Intraperitoneal injection of luseogliflozin (0.9 mg kg^-1) did not change MAP, HR, RBF, or creatinine clearance (CrCl) in SD rats (n = 7). Luseogliflozin significantly increased urine volume, which was associated with significantly increased urinary glucose excretion rates (P < 0.001). Similarly, luseogliflozin significantly increased urinary sodium excretion (from 0.07 ± 0.01 µmol min^-1 at baseline to 0.76 ± 0.08 µmol min^-1 at 120 min; P < 0.001). Furthermore, luseogliflozin resulted in significantly increased urinary pH (P < 0.001) and decreased urinary osmolality and urea concentration (P < 0.001) in SD rats. Similarly, in Nx SD rats (n = 5-6), luseogliflozin significantly increased urine volume and urinary glucose excretion (P < 0.001) without altering MAP, HR, RBF, or CrCl. Luseogliflozin did not elicit any significant effects on the other urinary parameters in Nx SD rats. These data indicate that SGLT2 inhibitor elicits direct tubular effects in non-diabetic rats with normal renal functions.

Figure 1

Urinary flow and glucose excretion in Protocol 1. Intravenous injection of luseogliflozin significantly increased urine flow (a) and glucose excretion (b) in both SD and Nx SD rats. SD, Sprague Dawley; Nx, 5/6 nephrectomized; vehicle, SD rats treated with vehicle; luseogliflozin, SD rats treated with luseogliflozin; Nx-vehicle, 5/6 Nx SD rats treated with vehicle; Nx-luseogliflozin, 5/6 Nx SD rats treated with luseogliflozin. Values are mean ± SEM. *P < 0.05, **P < 0.01  and ***P < 0.001 vs. baseline, ^# P < 0.05 and ^### P < 0.001 vs. vehicle, ⁺ P < 0.05 and ⁺⁺ P < 0.01 vs. Nx-vehicle.

Figure 2

Urinary sodium excretion in Protocol 1. Intravenous injection of luseogliflozin significantly increased urinary sodium excretion in SD rats. SD, Sprague Dawley; Nx, 5/6 nephrectomized; vehicle, SD rats treated with vehicle; luseogliflozin, SD rats treated with luseogliflozin; Nx-vehicle, 5/6 Nx SD rats treated with vehicle; Nx-luseogliflozin, 5/6 Nx SD rats treated with luseogliflozin. Values are mean ± SEM. *P < 0.05 and ***P < 0.001 vs. baseline, ^# P < 0.05, ^## P < 0.01 and ^### P < 0.001 vs. vehicle.

Figure 3

Urinary flow and glucose excretion in Protocol 2. Intraperitoneal injection of luseogliflozin significantly increased urinary flow (a) and glucose (b) excretion in both SD and Nx SD rats. SD, Sprague Dawley; Nx, 5/6 nephrectomized; vehicle, SD rats treated with vehicle; luseogliflozin, SD rats treated with luseogliflozin; Nx-vehicle, 5/6 Nx SD rats treated with vehicle; Nx-luseogliflozin, 5/6 Nx SD rats treated with luseogliflozin. Values are mean ± SEM. *P < 0.05, ** P < 0.01 and ***P < 0.001 vs. baseline, ^# P < 0.05, ^## P < 0.01 and ^### P < 0.001 vs. vehicle, ⁺ P < 0.05 and ⁺⁺⁺ P < 0.001 vs. Nx-vehicle.

Figure 4

Urinary sodium excretion in Protocol 2. Intraperitoneal injection of luseogliflozin significantly increased urinary sodium excretion in SD rats. SD, Sprague Dawley; Nx, 5/6 nephrectomized; vehicle, SD rats treated with vehicle; luseogliflozin, SD rats treated with luseogliflozin; Nx-vehicle, 5/6 Nx SD rats treated with vehicle; Nx-luseogliflozin, 5/6 Nx SD rats treated with luseogliflozin. Values are mean ± SEM. ***P < 0.001 vs. baseline, ^### P < 0.001 vs. vehicle.

Figure 5

Urinary pH and urea concentration in Protocol 2. Effect of intraperitoneal injection of luseogliflozin on urine pH (a) and urea concentration (b). SD, Sprague Dawley; Nx, 5/6 nephrectomized; vehicle, SD rats treated with vehicle; luseogliflozin, SD rats treated with luseogliflozin; Nx-vehicle, 5/6 Nx SD rats treated with vehicle; Nx-luseogliflozin, 5/6 Nx SD rats treated with luseogliflozin. Values are mean ± SEM. *P < 0.05 and ***P < 0.001 vs. baseline, ^### P < 0.001 vs. vehicle.

Figure 6

Urine osmolality and free water clearance in Protocol 2. Effect of intraperitoneal injection of luseogliflozin on urine osmolality (a) and free water clearance (b). SD, Sprague Dawley; Nx, 5/6 nephrectomized; vehicle, SD rats treated with vehicle; luseogliflozin, SD rats treated with luseogliflozin; Nx-vehicle, 5/6 Nx SD rats treated with vehicle; Nx-luseogliflozin, 5/6 Nx SD rats treated with luseogliflozin. Values are mean ± SEM. ***P < 0.001 vs. baseline, ^# P < 0.05 and ^### P < 0.001 vs. vehicle.