| Authors |
Wang XX, Jiang T, Shen Y, Caldas Y, Miyazaki-Anzai S, Santamaria H, Urbanek C,
Solis N, Scherzer P, Lewis L, Gonzalez FJ, Adorini L, Pruzanski M, Kopp JB,
Verlander JW, Levi M
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| Submitted By |
Moshe Levi on 7/30/2010 |
| Status |
Published |
| Journal |
Diabetes |
| Year |
2010 |
| Date Published |
11/1/2010 |
| Volume : Pages |
59 : 2916 - 2927 |
| PubMed Reference |
20699418 |
| Abstract |
OBJECTIVE: The pathogenesis of diabetic nephropathy is complex and involves
activation of multiple pathways leading to kidney damage. An important role for
altered lipid metabolism via sterol regulatory element binding proteins (SREBPs)
has been recently recognized in diabetic kidney disease. Our previous studies
have shown that the farnesoid X receptor (FXR), a bile acid-activated nuclear
hormone receptor, modulates renal SREBP-1 expression. The purpose of the present
study was then to determine if FXR deficiency accelerates type 1 diabetic
nephropathy in part by further stimulation of SREBPs and related pathways, and
conversely, if a selective FXR agonist can prevent the development of type 1
diabetic nephropathy. RESEARCH DESIGN AND METHODS: Insulin deficiency and
hyperglycemia were induced with streptozotocin (STZ) in C57BL/6 FXR KO mice.
Progress of renal injury was compared with nephropathy-resistant wild-type
C57BL/6 mice given STZ. DBA/2J mice with STZ-induced hyperglycemia were treated
with the selective FXR agonist INT-747 for 12 weeks. To accelerate disease
progression, all mice were placed on the Western diet after hyperglycemia
development. RESULTS: The present study demonstrates accelerated renal injury in
diabetic FXR KO mice. In contrast, treatment with the FXR agonist INT-747
improves renal injury by decreasing proteinuria, glomerulosclerosis, and
tubulointerstitial fibrosis, and modulating renal lipid metabolism, macrophage
infiltration, and renal expression of SREBPs, profibrotic growth factors, and
oxidative stress enzymes in the diabetic DBA/2J strain. CONCLUSIONS: Our
findings indicate a critical role for FXR in the development of diabetic
nephropathy and show that FXR activation prevents nephropathy in type 1
diabetes.
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