Empagliflozin ameliorates renal and metabolic derangements in obese type 2 diabetic mice by blocking advanced glycation end product–receptor axis

Abstract

Background: Although randomized clinical trials revealed that inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduced the risk of cardiovascular and renal events in patients with type 2 diabetes, the underlying molecular mechanisms remain to be elucidated. Since there is accumulating evidence that AGEs and their receptor (RAGE) play a crucial role in diabetes-related complications, we examined here whether empagliflozin ameliorates renal and metabolic derangements in db/db mice, an obese type 2 diabetes animal by blocking the AGE-RAGE axis. Methods: Eight-week-old db/db mice were fed a 0.045% empagliflozin diet (db/db + Empa) or normal diet (db/db) for 13 weeks. The same week-old db/ + m mice were maintained on normal diet (db/ + m) used as a control. At baseline and 13 weeks after intervention, biochemical analyses in the serum and urine were performed, and kidneys and adipose tissues were obtained for morphological, immunohistochemical, and reverse transcription-polymerase chain reaction analyses. Results: Empagliflozin treatment for 13 weeks significantly reduced AGEs, Nε-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), RAGE, NADPH oxidase-derived oxidative stress, inflammatory and fibrotic reactions in the kidneys of db/db mice of 21-week-old in association with attenuation of glomerular extracellular matrix accumulation, podocyte loss, proteinuria, and tubulointerstitial damage. Empagliflozin also reduced the AGE-RAGE-oxidative stress-induced inflammatory reactions in the adipose tissues of db/db mice, which was associated with restoration of adiponectin levels and decreased insulin resistance. Serum MG-H1 levels of control and db/db mice at 21 weeks of age were significantly associated with proteinuria, tubulointerstitial damage, tissue AGEs levels, and serum monocyte chemoattractant protein-1 and adiponectin (inversely) values. Conclusions: Our present findings suggest that empagliflozin could ameliorate renal and metabolic derangements in type 2 diabetes animals by attenuating the AGE-RAGE axis.