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.