Farnesoid X Receptor Modulates Renal Lipid Metabolism, Fibrosis, and Diabetic Nephropathy

Abstract

OBJECTIVE—Recent studies indicate an important role for nuclear receptors in regulating lipid and carbohydrate metabolism, fibrosis, and inflammation. Farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily. FXR is highly expressed in the liver, intestine, adrenal gland, and kidney. The primary bile acids are the highest affinity endogenous ligands for FXR. The effects of FXR agonists in diabetic kidney disease, the main cause of end-stage renal disease, however, have not been determined. RESEARCH DESIGN AND METHODS—To identify the effect of FXR activation in modulation of diabetic nephropathy, we treated 1) C57BL/6J mice on low-fat diet or high-fat diet with FXR agonists (GW4064 or cholic acid) for 1 week; 2) C57BLKS/J-db/db mice and their lean mates with GW4064 for 1 week; and 3) C57BL/6J-db/db mice and their lean mates with cholic acid for 12 weeks. RESULTS—We found that FXR agonists modulate renal sterol regulatory element–binding protein-1 (SREBP-1) expression and lipid metabolism and renal expression of profibrotic growth factors, proinflammatory cytokines, and oxidative stress enzymes and decrease glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria. In renal mesangial cells, overexpression of FXR or treatment with GW4064 also inhibited SREBP-1c and other lipogenic genes, transforming growth factor-β, and interleukin-6, suggesting a direct role of FXR in modulating renal lipid metabolism and modulation of fibrosis and inflammation. CONCLUSIONS—These results therefore indicate a new and important role for FXR in the kidney and provide new therapeutic avenues for the treatment of diabetic nephropathy.