TFF3 in renal pathobiology: a novel lipotoxicity regulator in male mice with diabetic kidney disease

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 remains unclear. To investigate the role of TFF3 in regulating lipotoxicity in DKD, male Tff3 -/- C57BL/6J mice were used in our study. The mice were divided into four groups: WT (wild type), WT-Tff3 -/- , Mod-WT (DKD model), and Mod-Tff3 -/- . The DKD model was established using a combination of high-fat diet and streptozotocin (STZ). Basic physiological parameters, including body weight and fasting blood glucose (FBG), were monitored biweekly. Glucolipid metabolism and renal functional parameters, including TC, TG, LDL-c, HDL-c, OGTT, ITT, UACR, and BUN, were detected by biochemical detection kits. Renal pathological examination methods including H&E and Oil Red O staining were used. Western blot analysis was performed to quantify the protein levels of SCAP, SREBP, AMPK, p-AMPK, ACC, and p-ACC in renal tissues. Our findings indicate that Tff3 deficiency in the kidney significantly alters renal lipid metabolism but not glucose metabolism. Tff3 -/- mice exhibited elevated levels of TC, TG, and LDL-c, but 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. In conclusion, Tff3 knockout could accelerate renal lipotoxicity by the AMPK/ACC and SCAP/SREBP signaling pathways in DKD progression, which provides a new perspective of DKD investigation.