FXR Modulates Renal Lipid Metabolism, Fibrosis and Diabetic Nephropathy

Abstract

Abstract 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. To identify the effect of FXR activation in modulation of diabetic nephropathy, we have treated 1) C57BL/6J mice on low fat diet or high fat diet with FXR agonists (GW4064 or cholic acid) for one week; 2) C57BLKS/J-db/db mice and their lean mates with GW4064 for one week; and 3) C57BL/6J-db/db mice and their lean mates with cholic acid for 12 weeks. We found that FXR agonists modulate renal SREBP-1 expression and lipid metabolism, as well as 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, TGF-β, and IL-6, suggesting a direct role of FXR in modulating renal lipid metabolism and modulation of fibrosis and inflammation. These results therefore indicate a new and an important role for FXR in the kidney and provide new therapeutic avenues for the treatment of diabetic nephropathy.