| Authors |
Wang XX, Jiang T, Shen Y, Adorini L, Pruzanski M, Gonzalez FJ, Scherzer P, Lewis
L, Miyazaki-Anzai S, Levi M
|
| Submitted By |
Moshe Levi on 3/24/2010 |
| Status |
Published |
| Journal |
American journal of physiology. Renal physiology |
| Year |
2009 |
| Date Published |
12/1/2009 |
| Volume : Pages |
297(6) : F1587 - F1596 |
| PubMed Reference |
19776172 |
| Abstract |
Diet-induced obesity is associated with proteinuria and glomerular disease in
humans and rodents. We have shown that in mice fed a high-fat diet, increased
renal expression of the transcriptional factor sterol-regulatory element binding
protein-1 (SREBP-1) plays a critical role in renal lipid accumulation and
increases the activity of proinflammatory cytokines and profibrotic growth
factors. In the current study, we have determined a key role of the farnesoid X
receptor (FXR) in modulating renal SREBP-1 activity, glomerular lesions, and
proteinuria. We found that feeding a Western-style diet to DBA/2J mice results
in proteinuria, podocyte loss, mesangial expansion, renal lipid accumulation,
and increased expression of proinflammatory factors, oxidative stress, and
profibrotic growth factors. Treatment of these mice with the highly selective
and potent FXR-activating ligand 6-alpha-ethyl-chenodeoxycholic acid (INT-747)
ameliorates triglyceride accumulation by modulating fatty acid synthesis and
oxidation, improves proteinuria, prevents podocyte loss, mesangial expansion,
accumulation of extracellular matrix proteins, and increased expression of
profibrotic growth factors and fibrosis markers, and modulates inflammation and
oxidative stress. Our results therefore indicate that FXR activation could
represent an effective therapy for treatment of abnormal renal lipid metabolism
with associated inflammation, oxidative stress, and kidney pathology in patients
affected by obesity.
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