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.
Highlights
To manage type 2 diabetes mellitus, blockade of glucose reabsorption at the proximal tubule using sodium–glucose cotransporter 2 (SGLT2) inhibitors have been recently applied[1, 2]
We found that intraperitoneal administration of vehicle did not change urine flow or urinary sodium excretion
To avoid any systemic changes, the present study utilized acute renal clearance method to examine the effects of luseogliflozin on renal hemodynamics and tubular functions
Summary
To manage type 2 diabetes mellitus, blockade of glucose reabsorption at the proximal tubule using sodium–glucose cotransporter 2 (SGLT2) inhibitors have been recently applied[1, 2]. A clinical study reported that treatment with canagliflozin, the SGLT2 inhibitor, significantly increased urinary sodium excretion in patients with type 2 diabetes[8] These findings suggest that SGLT2 inhibitor-induced blood pressure reduction is accompanied by natriuresis in patients with metabolic syndrome and diabetes. It is of particular importance that the pharmacological effects of SGLT2 inhibitors in non-diabetic subjects are studied to minimize any indirect influence induced by changes in blood glucose levels. In this regard, a study with pooled urine reported that treatment with an SGLT2 inhibitor increased the 24-h urine volume, urinary glucose, and sodium excretion in non-diabetic mice[12]. We examined the effects of a SGLT2 inhibitor on renal hemodynamics and functions in 5/6 nephrectomized (Nx) rat, a model of CKD
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