Role of Thioredoxin-Interacting Protein in Diabetic Fatty Kidney Induced by Advanced Glycation End-Products.

Abstract

Advanced glycation end-products (AGEs) have been identified as the etiological factors associated with the fatty kidney. Thioredoxin-interacting protein (TXNIP) might be a mediator involved in AGE-induced fatty kidney. This study focused on investigating how TXNIP affected the AGE-mediated renal lipid deposition. In an in vivo experiment, the db/db mice injected with the lentiviral vector encoding shRNA targeting TXNIP were given the AIN-76 basal or the high-AGE diet. TXNIP-targeting siRNA-transfected human renal proximal tubular epithelial (HK-2) cells were exposed to AGE-BSA in a study in vitro. The results showed that the silencing of TXNIP reduced tubular lipid droplets and intracellular cholesterol content, as well as upregulated Insig-1 and downregulated HMGCoAR, LDLr, nSREBP-2, and SCAP in the kidneys of the db/db mice, the high-AGE-diet-fed db/db mice, and AGE-BSA-treated HK-2 cells. Furthermore, AGE-BSA enhanced SCAP-SREBP-2 complex formation while promoting their transportation to the Golgi apparatus. However, these could be inhibited by TXNIP silencing in the HK-2 cells. The above findings indicated that TXNIP knockdown mitigated the accumulation of renal tubular lipids in diabetes through the regulation of SCAP, thereby inhibiting the SCAP-SREBP-2 signaling pathway, resulting in reduced cholesterol uptake and synthesis. Therefore, TXNIP might be a potential therapeutic target to treat a diabetic fatty kidney.