Diabetes severely affects kidney function, with 40% of patients developing diabetic kidney disease (DKD), and diabetes being a major contributor to end-stage renal disease. Renal lipotoxicity is increasingly relevant as DKD progresses, triggering kidney injury through inflammation and oxidative stress. The AMPK/ACC and SCAP/SREBP signalling pathways are heavily involved in glycolipid metabolism and lipid deposition homeostasis, and their modulation exacerbates DKD through inflammation, mitochondrial damage and dysregulation of cholesterol homeostasis.

The peptide trefoil factor 3 (TFF3) is secreted by epithelial cells and plays a role in glucolipid metabolic regulation within the endocrine organs. TFF3 deficiency reduces lipid accumulation in the liver after a prolonged high-fat diet in mice, and urinary TFF3 increases with the onset and development of DKD in humans.

Zhang, Lai and coworkers hypothesised that TFF3 had a regulatory role in renal lipotoxicity in DKD through the AMPK/ACC and SCAP/SREBP signalling pathways. They found that TFF3 knockout in the DKD mouse model caused exacerbated renal lipid deposition and injury compared with controls. Western blot analysis of kidney samples found reduced levels of AMPK and ACC alongside dramatically elevated levels of SCAP and SREBP in the DKD mouse model compared with the wild-type controls. This suggests that TFF3 plays an important role in modulating the AMPK/ACC/SCAP/SREBP signalling pathways and has the potential to provide a therapeutic target for DKD.

Read the full article in Journal of Endocrinology https://doi.org/10.1530/JOE-25-0303