Abstract
Background: Advanced glycation end products (AGEs) are pathogenic factors of renal tubular lipid accumulation and play a negative role in diabetic kidney disease (DKD). Glucose cotransporter (SGLT) 2 inhibition offers strong renoprotection in the progression of DKD. The aim of the current study was to investigate the effects of empagliflozin (EMPA, a potent and selective SGLT2 inhibitor) on AGEs-induced renal tubular lipid accumulation in both diabetic mice fed with a high-AGEs diet and AGEs-treated cultured human renal proximal tubular epithelial (HK-2) cells. Methods: In vivo, EMPA was used to treat db/db mice fed a high-AGEs diet or an AIN-76 basal diet. In an in vitro study, HK-2 cells were treated with AGEs-bovine serum albumin (BSA) and/or EMPA. Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) translocation was detected by confocal microscopy. Results: EMPA reduced tubular lipid droplets and intracellular cholesterol content, as well as the expression of proteins involved in the synthesis and absorption of cholesterol in the kidneys of basal diet-fed db/db mice, high-AGEs diet-fed db/db mice and AGEs-BSA-treated HK-2 cells. AGEs-BSA loading promoted the formation of SCAP-SREBP-2 complexes and enhanced the transport of the complexes to the Golgi, but these effects were markedly inhibited by EMPA in HK-2 cells. EMPA reduced renal inflammation both in basal diet-fed db/db mice and high-AGEs diet-fed db/db mice, and suppressed NLRP3 inflammasome activation in AGEs-BSA-treated HK-2 cells. In addition, EMPA reduced the serum AGEs level in vivo and inhibited renal tubular endoplasmic reticulum (ER) stress and receptor of AGEs (RAGE) expression both in vivo and in vitro. Conclusions: EMPA attenuated AGEs synthesis and inhibited the AGEs-RAGE signaling pathway, thereby suppressing ER stress and inhibiting abnormal cholesterol metabolism and release of inflammatory cytokines, thus alleviating renal tubular lipid accumulation and inflammation.
Pharmacological inhibition of fatty acid oxidation reduces atherosclerosis progression by suppression of macrophage NLRP3 inflammasome activation
