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.

Does SGLT2 Inhibition Affect Sympathetic Nerve Activity in Type 2 Diabetes?

“…A direct tubular effect was observed after intraperitoneal injection of luseogliflozin in experimental models without diabetes, regardless of the change in plasma glucose levels and in the absence of hemodynamic renal effects. This is in support of the notion that the mechanism of tubulo-glomerular feedback is unlikely to be triggered [89]. These data provide evidence for an important cross-talk between sympathetic nervous system regulation and SGLT2 inhibition.…”

Diuretic Effects of Sodium Glucose Cotransporter 2 Inhibitors and Their Influence on the Renin-Angiotensin System

“…The diuretic actions of SGLT2 inhibitors presumably play an important role in cardioprotection, as shown in the EMPA-REG OUTCOME study and the CANVAS program. SGLT2 inhibitors have acutely caused an increase in urinary sodium excretion in non-diabetic rats [21] and in diabetic rats [22,23]. In type 2 diabetic patients, increased urinary sodium excretion has been observed during the early phase of treatment with canagliflozin [16,18,19] and empagliflozin [24].…”

“…Studies in db/db mice have also shown that hyperglycemia increases kidney volume without enlarging glomeruli and that treatment with SGLT2 inhibitors causes glomerular hypertrophy, glomeruli redistribution, and reduced kidney volume, with no effects on GFR [66]. Similarly, acute administration of luseogliflozin has not changed GFR in non-diabetic rats [21]. However, empagliflozin has resulted in a significant decrease in GFR in Akita mice [67].…”

Safety and Efficacy of adding Dapagliflozin to Furosemide in Type 2 Diabetic Patients with Decompensated Heart Failure and Reduced Ejection Fraction

“…The diuretic actions of SGLT-2 inhibitors presumably play an important role in cardioprotection, as shown in the EMPA-REG OUTCOME study and the CANVAS program. SGLT-2 inhibitors have acutely caused an increase in urinary sodium excretion in non-diabetic [53] and diabetic rats [54,55].Our study showed that addition of dapagli ozin to furosemide actually improved all studied diuresis parameters including urine output, total uid balance as well as uid balance/diuretic dose. In a small randomized, placebocontrolled, double-blind trial, involving 75 subjects with T2DM, dapagli ozin has been shown to reduce plasma volume in a similar way to thiazide diuretics, but dapagli ozin has a more enduring diuretic effect than other diuretics [17].…”