Abstract
BackgroundRenal proximal tubular sodium and glucose reabsorption are regulated by the sodium-glucose cotransporter (SGLT2). Changes in this transporter can play a role in hyperglycaemia and reactive oxygen species (ROS) production. We demonstrated increased glucose absorption in proximal tubule membrane vesicles and increased expression of SGLT2 in hypertensive rats. Here we investigated Angiotensin II (Ang II) -dependent SGLT2 expression induction and the role of SGLT2 induction in the development of Ang II-dependent kidney damage. The aim of this study was to determine whether SGLT2 induction by Ang II is associated with Ang II-dependent kidney damage. We propose the following objectives a) to demonstrate that Ang II induces SGLT2 expression and b) to demonstrate that prevention of SGLT2 expression and activity prevent Ang II-induced kidney damage.MethodsWe used chronic Ang II infusion as a model of kidney damage in male Wistar rats and evaluated systolic blood pressure by telemetric methods. SGLT2 mRNA and protein expression were evaluated by PCR and immunoblotting. SGLT2 activity was evaluated in brush border membrane vesicles by measuring glucose uptake. ROS production was measured by confocal microscopy. The glomerular filtration rate (GFR) was evaluated by the inulin excretion method, and urinary protein excretion was evaluated by the Bradford method. Biological parameter evaluations were performed, after two weeks of infusion of Ang II. We compared the effects of Angiotensin II (AT1) receptor blockade by Losartan and SGLT2 inhibition by Empagliflozin both as monotherapy treatments and in combination on the development of kidney damage.ResultsChronic Ang II infusion led to a blood pressure elevation and increased SGLT2 mRNA expression and activity as well as kidney damage, as reflected by increased ROS production, decreased GFR and increased urinary protein excretion. AT1 receptor blockade prevented all these changes. By contrast, SGLT2 inhibition did not affect blood pressure and had a small effect on kidney damage. However, the combination of both drugs resulted in the potentiation of the effects observed by AT1 receptor blockade alone.ConclusionsWe suggest that Ang II-dependent increased SGLT2 induction is one mechanism by which Ang II induces kidney damage.
Highlights
Renal proximal tubular sodium and glucose reabsorption are regulated by the sodium-glucose cotransporter (SGLT2)
In this study we evaluated the effect of elevated Angiotensin II (Ang) II concentration on Sodium-Glucose Cotransporter type 2 (SGLT2) expression and the effect of this increased SGLT2 expression on blood pressure (BP) and kidney damage by comparing prevention of the Angiotensin II (Ang II)-induced kidney damage by either Angiotensin II receptor type 1 (AT1) receptor blockade (Losartan), SGLT2 inhibition (Empagliflozin) monotherapy or by the combination of both treatments
In conclusion, we demonstrated that Ang II infusion is associated with kidney damage as well as increased SGLT2 cotransporter expression
Summary
Renal proximal tubular sodium and glucose reabsorption are regulated by the sodium-glucose cotransporter (SGLT2). Changes in this transporter can play a role in hyperglycaemia and reactive oxygen species (ROS) production. A post-hoc analysis of patients with a history of hypertension and who did not meet the BP goal of less than 130/80 mmHg at baseline showed that 29.5–37.5% of such patients assigned to dapagliflozin achieved the goal at week 24 compared with 8.8% of patients assigned to placebo [8] These results suggest that SGLT2 may be associated with the mechanisms of hypertension development. We reported increased glucose absorption in proximal tubule membrane vesicles and increased expression of SGLT2 in response to renovascular hypertension in rats. Ang II induced hypertension and increased chemokines and reactive oxygen species (ROS), which may be major contributors to the development of kidney failure [11]
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