Farnesoid X receptor modulates renal lipid metabolism, fibrosis, and diabetic nephropathy.
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.


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-beta, 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.
Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, 4200 East 9th Ave., Denver, CO 80262, USA.
Tao
T
Jiang
Xiaoxin X
XX
Wang
Pnina
P
Scherzer
Paul
P
Wilson
James
J
Tallman
Hideaki
H
Takahashi
Jinping
J
Li
Mieko
M
Iwahashi
Eileen
E
Sutherland
Lois
L
Arend
Moshe
M
Levi
D000818:Animals; D004268:DNA-Binding Proteins / Q000819:agonists / Q000502:physiology*; D003928:Diabetic Nephropathies / Q000503:physiopathology*; D018752:Diet, Fat-Restricted; D004041:Dietary Fats; D005355:Fibrosis; D007249:Inflammation; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008055:Lipids / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology; D014157:Transcription Factors / Q000819:agonists / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D004268:DNA-Binding Proteins; D004041:Dietary Fats; D008055:Lipids; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C497388:Srebf1 protein, mouse