Adipocyte Fatty Acid Binding Protein (A-FABP) is a pathological mediator of obesity-related renal dysfunction

Abstract

Background and Aims Chronic kidney disease (CKD) is an emerging global public health problem which is characterized by irreversible deterioration of kidney function and can gradually progress to end-stage renal disease (ESRD). Obesity is the major risk factor of type 2 diabetes, hypertension and cardiovascular disease which are shown to promote CKD. Obesity is also an independent risk factor for the development and progression of this disease. Adipocyte fatty acid binding protein (A-FABP) is an adipokine expressed in adipocytes, macrophages and endothelial cells. Its circulating level is increased in obese patients and is closely associated with various obesity-related cardio-metabolic diseases. Emerging clinical evidences suggest that A-FABP is implicated in renal dysfunction. Our clinical findings also showed that circulating levels of A-FABP are independently associated with nephropathy staging and macrovascular complications of type 2 diabetic patients. However, the underlying mechanism whereby A-FABP mediates renal dysfunction is so far not explored. Here we investigated the pathological role of A-FABP in the development of renal dysfunction associating with obesity. Methods and Materials A-FABP knockout (KO) mice and their wildtype (WT) littermates were fed with either standard chow (STC) or high fat high cholesterol (HFHC) diet for 20 weeks. Another batch of mice was fed with HFHC diet in the presence of pharmacological inhibitor of A-FABP, BMS309403 (BMS). Various serum and urine biochemical parameters, morphological change and lipid accumulation in kidney were determined. Results HFHC-diet feeding increased the circulating level and renal expression of A-FABP in WT mice. Pharmacological inhibition of A-FABP by treatment with BMS not only significantly attenuated HFHC diet-induced hyperglycemia and hyperinsulinemia but also alleviated renomegaly in WT mice which was accompanied by reduced glomerulus volume, glycogen deposition and fibrotic area. Treatment of BMS markedly reduced diet-induced urinary albumin level comparing to respective controls. HFHC diet-induced renal lipid accumulation was remarkably attenuated in A-FABP KO mice as indicated by reduced oil droplets and diminished renal triglyceride levels when compared to respective WT controls. A-FABP deficiency also protects against the development of diet-induced hypertension in mice. The expression of A-FABP was significantly increased in the renal sections of HFHC diet-induced WT mice comparing with that of the STC-fed mice and was co-localized with endothelial cell marker CD31. In addition, treatment of palmitate significantly induced the expression of A-FABP in the human umbilical vein endothelial cells (HUVECs) compared to the vehicle-treated control.