Renal Anti-Fibrotic Effect of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension.

Background: Clinical trials have shown that empagliflozin (Empa), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, promotes nephroprotective effects in diabetic patients. The mechanisms underlying nephroprotection are not com- pletely known and it is not known whether the renal benefi- cial action is present even in non-diabetic kidney disease. The aim of this study was to evaluate the effect of Empa ad- ministration on the development of renal fibrosis in an ex- perimental model of angiotensin II (Ang II)-dependent hy- pertension. Methods: Sprague Dawley rats (n = 31) were di- vided into 4 experimental groups. Ang II (200 ng/kg/min, osmotic minipumps, s.c., n = 9) or Ang II + Empa (10 mg/kg/ day, per os, n = 10) were administered for 2 weeks. Control rats were treated with placebo (physiological saline, n = 6), and another group was treated with placebo plus Empa (n = 6) for the same period. Blood pressure (plethysmographic method) was measured at the beginning and at the end of the experimental protocol. After 2 weeks, the rats were eu- thanized and the kidneys were excised for histomorphomet- ric evaluation of glomerular and tubulo-interstitial fibrosis and for the immunohistochemical evaluation of inflamma- tory infiltrates (monocytes/macrophages) and types I and IV collagen expression. Results: The administration of Ang II re- sulted in an increase in blood pressure (p < 0.01), glomerular (p < 0.05) and tubulo-interstitial (p < 0.01) fibrosis, renal in- flammatory infiltrates (p < 0.01) and type I (p < 0.01) and type IV collagen expression (p < 0.05) compared to the control group. Treatment with Empa did not significantly modify the increase in blood pressure due to Ang II, but prevented the development of renal glomerular and tubulo-interstitial fi- brosis, and the increase in inflammatory infiltrates and types I and IV collagen expression in Ang II-treated rats (p < 0.01). Conclusions: These data demonstrate that the treatment with Empa prevents the development of renal fibrosis in AngII-dependent hypertension. In Ang II-dependent hyperten- sion, the anti-fibrotic effect due to SGLT2 inhibition is caused by the reduction of inflammatory infiltrates and it is inde- pendent on the modulation of blood pressure increase.