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Trefoil factor 3 (TFF3) is a small peptide with complex activities in different diseases. Our previous studies have indicated that TFF3 can mediate gut-kidney crosstalk in diabetic kidney disease (DKD), but the underlying mechanism remain unclear. To investigate the role of TFF3 in regulating lipotoxicity in DKD, male Tff3 -/- C57BL6J mice were used. The mice were divided into 4 groups: WT (Wild Type), WT- Tff3 -/- , Mod-WT (DKD Model), Mod- Tff3 -/- ; The DKD model was established using a combination of high-fat diet and streptozotocin (STZ). Basic physiological parameters, including body weight (BW) and fasting blood glucose (FBG), were monitored biweekly. Glucolipid metabolism and renal functional parameters including TC, TG, LDL, HDL, OGTT, ITT, UACR and BUN were detected by biochemical detection kits. The renal pathological examination methods including H&E and Oil Red O staining were used. Western blot analysis was performed to quantify the protein leves of SCAP, SREBP, AMPK, p-AMPK, ACC and p-ACC in renal tissues. Our findings indicate that Tff3 deficiency significantly alters renal lipid metabolism but not glucose metabolism. Tff3 -/- mice exhibited elevated levels of TC, TG, and LDL, with no significant changes in HDL or the AUC of OGTT and ITT; Additionally, Tff3 deficiency accelerates renal pathological changes, including lipid accumulation; Furthermore, Tff3 -/- mice showed up-regulation of SCAP and SREBP expression and down-regulation of p-AMPK and p-ACC in the context of DKD. Conclusion, Tff3 knockout could accelerate lipotoxicity by AMPK/ACC-SCAP/SREBP signaling pathway in DKD progression, which provides a new perspective of DKD investigation.