Role of sodium/glucose cotransporter inhibition on a rat model of angiotensin II–dependent kidney damage

Abstract

Background 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. 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. Methods We 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. Results Chronic 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. Conclusions We suggest that Ang II-dependent increased SGLT2 induction is one mechanism by which Ang II induces kidney damage. Electronic supplementary material The online version of this article (10.1186/s12882-019-1490-z) contains supplementary material, which is available to authorized users.

Crosstalk between Sodium–Glucose Cotransporter Inhibitors and Sodium–Hydrogen Exchanger 1 and 3 in Cardiometabolic Diseases

“…In this study, Losartan prevented renal damage, whereas EMPA produced a minimal protective effect. Nonetheless, EMPA attenuated oxidative stress [ 122 ]. Clinical trials have consistently shown that SGLT2i reduces BP [ 123 ].…”

Dapagliflozin Alleviates Renal Fibrosis by Inhibiting RIP1-RIP3-MLKL-Mediated Necroinflammation in Unilateral Ureteral Obstruction

“…Our study demonstrates that treatment with Dapa (10 mg/kg/d) alleviates renal fibrosis from UUO by inhibiting necroinflammation, oxidative stress, and apoptosis. This is supported by a variety of nondiabetic CKD studies, such as adenine-induced CKD (Ali et al, 2019) and angiotensin II-dependent kidney damage (Reyes-Pardo et al, 2019). However, an interesting result was observed from subtotal (5/6) nephrectomy.…”

Therapeutic effects of lisinopril and empagliflozin in a mouse model of hypertension-accelerated diabetic kidney disease

“…Accordingly, empagliflozin and dapagliflozin have demonstrated no effect or attenuate renal endpoints in normotensive diabetes models with features of mild-moderate kidney pathology, including db/db mice (1,16,19,38,55,58). Empagliflozin has been demonstrated to prevent development of glomerular and tubulointerstitial fibrosis, but not GFR loss, following angiotensin II infusion or 5/6 nephrectomy in non-diabetic rodents (8,44,58). While dapagliflozin showed no glomeruloprotective effect when administered one week after 5/6 nephrectomy(62), canagliflozin treatment starting one week after angiotensin II infusion has been reported to improve GFR and improve glomerulosclerosis in normoglycemic mice (34).…”