Limits...
Diabetic nephropathy is accelerated by farnesoid X receptor deficiency and inhibited by farnesoid X receptor activation in a type 1 diabetes model.

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 - Diabetes (2010)

Bottom Line: Progress of renal injury was compared with nephropathy-resistant wild-type C57BL/6 mice given STZ.To accelerate disease progression, all mice were placed on the Western diet after hyperglycemia development.The present study demonstrates accelerated renal injury in diabetic FXR KO mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Colorado Denver, and VA Medical Center, Aurora, Colorado, USA.

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.

Show MeSH

Related in: MedlinePlus

Diabetic FXR KO kidney showed increased lipid accumulation. A: Oil red O staining of kidney sections and kidney lipid content showing lipid accumulation in diabetic FXR KO kidneys. G, glomerulus. B: Analysis of renal mRNA expression by quantitative real-time PCR for SREBP-1c, FAS, ACC, SCD-1, LDLR, and LOX-1 in isolated glomeruli. *P < 0.05 vs. diabetic wild-type C57BL/6J mice on WD or as specified (n = 6 mice per group). (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2963551&req=5

Figure 3: Diabetic FXR KO kidney showed increased lipid accumulation. A: Oil red O staining of kidney sections and kidney lipid content showing lipid accumulation in diabetic FXR KO kidneys. G, glomerulus. B: Analysis of renal mRNA expression by quantitative real-time PCR for SREBP-1c, FAS, ACC, SCD-1, LDLR, and LOX-1 in isolated glomeruli. *P < 0.05 vs. diabetic wild-type C57BL/6J mice on WD or as specified (n = 6 mice per group). (A high-quality digital representation of this figure is available in the online issue.)

Mentions: We found that FXR deficiency caused increased kidney neutral lipid accumulation in both glomeruli and tubulointerstitium, as determined by oil red O staining, and biochemical lipid analysis revealed increased kidney triglyceride and cholesterol content (Fig. 3A). To explore the mechanism by which FXR regulates renal lipid accumulation, we investigated pathways regulating renal lipid metabolism. In glomeruli isolated from diabetic FXR KO mice, we found significantly increased expression of SREBP-1c and its target genes fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase-1 (SCD-1), which mediate fatty acid and triglyceride synthesis. In addition, we observed increased expression of LDL receptor and lectin-like oxidized LDL receptor-1 (LOX-1), which mediate cholesterol and oxidized LDL uptake (Fig. 3B).


Diabetic nephropathy is accelerated by farnesoid X receptor deficiency and inhibited by farnesoid X receptor activation in a type 1 diabetes model.

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 - Diabetes (2010)

Diabetic FXR KO kidney showed increased lipid accumulation. A: Oil red O staining of kidney sections and kidney lipid content showing lipid accumulation in diabetic FXR KO kidneys. G, glomerulus. B: Analysis of renal mRNA expression by quantitative real-time PCR for SREBP-1c, FAS, ACC, SCD-1, LDLR, and LOX-1 in isolated glomeruli. *P < 0.05 vs. diabetic wild-type C57BL/6J mice on WD or as specified (n = 6 mice per group). (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2963551&req=5

Figure 3: Diabetic FXR KO kidney showed increased lipid accumulation. A: Oil red O staining of kidney sections and kidney lipid content showing lipid accumulation in diabetic FXR KO kidneys. G, glomerulus. B: Analysis of renal mRNA expression by quantitative real-time PCR for SREBP-1c, FAS, ACC, SCD-1, LDLR, and LOX-1 in isolated glomeruli. *P < 0.05 vs. diabetic wild-type C57BL/6J mice on WD or as specified (n = 6 mice per group). (A high-quality digital representation of this figure is available in the online issue.)
Mentions: We found that FXR deficiency caused increased kidney neutral lipid accumulation in both glomeruli and tubulointerstitium, as determined by oil red O staining, and biochemical lipid analysis revealed increased kidney triglyceride and cholesterol content (Fig. 3A). To explore the mechanism by which FXR regulates renal lipid accumulation, we investigated pathways regulating renal lipid metabolism. In glomeruli isolated from diabetic FXR KO mice, we found significantly increased expression of SREBP-1c and its target genes fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase-1 (SCD-1), which mediate fatty acid and triglyceride synthesis. In addition, we observed increased expression of LDL receptor and lectin-like oxidized LDL receptor-1 (LOX-1), which mediate cholesterol and oxidized LDL uptake (Fig. 3B).

Bottom Line: Progress of renal injury was compared with nephropathy-resistant wild-type C57BL/6 mice given STZ.To accelerate disease progression, all mice were placed on the Western diet after hyperglycemia development.The present study demonstrates accelerated renal injury in diabetic FXR KO mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Colorado Denver, and VA Medical Center, Aurora, Colorado, USA.

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.

Show MeSH
Related in: MedlinePlus