FABP4 inhibition protects renal tubular cells and ameliorates renal inflammation in diabetic kidney disease.

Diabetic kidney disease (DKD) is a common complication associated with diabetes mellitus (DM). Fatty acid binding protein (FABP) 4 is a small cytoplasmic lipid chaperone that is up-regulated in DKD. This study aims to elucidate whether FABP4 could play a critical role and serve as a potential therapeutic target in DKD. In a clinical observational study, DKD patients and non-DKD subjects were enrolled and their circulating FABP4 levels were analyzed. The renoprotective effects of FABP4 inhibition were evaluated in vivo and in vitro using db/db mice and high glucose-induced human kidney proximal tubular epithelial cells, respectively. Circulating FABP4 was up-regulated in clinical patients and mice with DKD. The inhibition of FABP4 with an orally administered inhibitor ameliorated insulin resistance and renal function in DKD mice, as evidenced by decreased systemic inflammation as well as improved serum creatinine and BUN levels, kidney weight to body weight ratio, and urine albumin-to-creatinine ratio. FABP4 inhibition also reduced renal tubular injury, fibrosis, and macrophage infiltration in DKD mice. Furthermore, FABP4 inhibition down-regulated the inflammatory, fibrotic, and cell apoptotic protein expressions in kidney tissues of DKD mice and in high glucose-induced renal proximal tubular epithelial cells. On the other hand, FABP4 directly caused cellular inflammation, fibrosis, and apoptosis via NF-κB activation in renal tubular epithelial cells. Altogether, FABP4 might induce renal inflammation and renal tubular epithelial cell damage during the pathological process of DKD. Future clinical studies may be required to validate whether FABP4 inhibition can serve as a novel therapeutic strategy for DKD.