Beneficial Effects of Empagliflozin Are Mediated by Reduced Renal Inflammation and Oxidative Stress in Spontaneously Hypertensive Rats Expressing Human C-Reactive Protein

Abstract

Gliflozins (inhibitors of sodium-glucose cotransporter 2) show many beneficial actions beyond their antidiabetic effects. The underlying mechanisms of these additional protective effects are still not well understood, especially under non-diabetic conditions. Therefore, we analyzed the effects of empagliflozin in young (3-month-old) and adult (12-month-old) male spontaneously hypertensive rats (SHR) expressing human C-reactive protein (CRP) in the liver. SHR-CRP rats are a non-diabetic model of metabolic syndrome, inflammation, and organ damage. Empagliflozin was given in a daily dose of 10 mg/kg body weight for 8 weeks. Both age groups of SHR-CRP rats treated with empagliflozin had lower body weight, decreased weight of fat depots, reduced ectopic fat accumulation in the liver and kidneys, and decreased levels of plasma insulin and β-hydroxybutyrate. Empagliflozin effectively reduced ectopic renal fat accumulation, and was associated with decreased inflammation. Exclusively in young rats, decreased microalbuminuria after empagliflozin treatment was accompanied by attenuated oxidative stress. In adult animals, empagliflozin also improved left ventricle function. In conclusion, in young animals, the beneficial renoprotective effects of empagliflozin could be ascribed to reduced lipid deposition in the kidney and the attenuation of oxidative stress and inflammation. In contrast, hepatic lipid metabolism was ameliorated in adult rats.

Empagliflozin Is Not Renoprotective in Non-Diabetic Rat Models of Chronic Kidney Disease

“…Similar to our [ 21 , 22 , 23 ] and other investigations [ 13 , 19 ], we have found that relative kidney weight was increased in FHH and UNX-HS rats. Whether this increase is associated with the dilatation of tubular lumen due to SGLT-2-induced diuresis or due to tubular cell hypertrophy remains to be determined.…”

“…Similarly, we did not demonstrate the improvement of cardiac function in hereditary hypertriglyceridemic rats, in which beneficial effects were mediated mainly through the improvement of hepatic lipid metabolism [ 21 ]. In contrast, in SHR-CRP rats, empagliflozin benefit was based on reduced renal inflammation and oxidative stress [ 23 ], which is in line with the findings of Ali et al [ 18 ], who also demonstrated a reduction in renal inflammation and ROS production in adenine-induced CKD. In addition, several studies ascribed renoprotection to the anti-fibrotic effects of gliflozins [ 17 , 19 , 28 ].…”

“…In addition, Ali et al [ 18 ] demonstrated the beneficial dose-dependent effects of canagliflozin (10 and 25 mg/kg/day) on adenine-induced CKD, demonstrating the improvement of renal parameters (albuminuria, creatinine clearance, and plasma urea) together with the attenuation of inflammation and oxidative stress. We cannot offer a plausible explanation for a lack of any positive effects of the generally accepted dose of empagliflozin in our experimental CKD models, although positive effects were obtained in our previous studies with hypertensive rat strains [ 22 , 23 ]. However, we cannot exclude the possibility that eight weeks following nephrectomy or 2K1C were insufficient for appropriate CKD development, although both of the other researchers and our previous experiments demonstrated a significant increase in proteinuria and a maximal decrease in creatinine clearance after the procedure [ 29 , 30 , 31 , 32 ].…”

“…Empagliflozin (Jardiance, Boehringer, Ingelheim, Germany), at a dose of 10 mg/kg/day, was mixed into the Altromin diet (so that the composition of both diets was the same) and given for 8 weeks. The amount of empagliflozin added to the diet was calculated according to our previous studies [ 21 , 22 , 23 ]. All procedures and experimental protocols were approved by the Ethical Committee of the Institute of Physiology, Czech Academy of Sciences (Protocol Nr.…”

“…Our previous studies in three non-diabetic hypertensive models (hypertensive Ren-2 transgenic rats, hereditary hypertriglyceridemic rats, and spontaneously hypertensive rats expressing the human CRP gene) [ 21 , 22 , 23 ] demonstrated the beneficial effects of SGLT-2 inhibition without a glucose-lowering effect. In all these models, empagliflozin treatment led to a reduction in body weight and visceral adiposity, while the additional effects depended on the model used—an improvement of metabolic parameters and hepatic metabolism (hHTG), a reduction in blood pressure (TGR), and the attenuation of oxidative stress and inflammation in kidneys (SHR-CRP).…”