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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.

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Related in: MedlinePlus

INT-747 treatment showed antifibrotic, anti-inflammatory, and antioxidative effects on diabetic DBA/2J mice. A: Renal TGF-β1 mRNA expression determined by quantitative real-time PCR. B: Immunofluorescence staining of kidney sections for fibronectin. The expression level of fibronectin was normalized to that in the control group. C: Expression of α-SMA in kidney determined by quantitative real-time PCR and immunohistologic staining. FSP-1 mRNA expression in kidney was determined by quantitative real-time PCR. D: Immunofluorescence staining of kidney sections for synaptopodin (red) and CD68 (green). E: Renal NF-κB p65 subunit mRNA expression by quantitative real-time PCR and NF-κB activation determined by DNA binding assay. F: Nox-2 and p22-phox mRNA expression in kidney determined by quantitative real-time PCR. Oxidative carbonylation of proteins in kidney homogenate was measured by ELISA. *P < 0.05 vs. CON; **P < 0.05 vs. STZ (n = 6 mice per group). (A high-quality digital representation of this figure is available in the online issue.)
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Figure 5: INT-747 treatment showed antifibrotic, anti-inflammatory, and antioxidative effects on diabetic DBA/2J mice. A: Renal TGF-β1 mRNA expression determined by quantitative real-time PCR. B: Immunofluorescence staining of kidney sections for fibronectin. The expression level of fibronectin was normalized to that in the control group. C: Expression of α-SMA in kidney determined by quantitative real-time PCR and immunohistologic staining. FSP-1 mRNA expression in kidney was determined by quantitative real-time PCR. D: Immunofluorescence staining of kidney sections for synaptopodin (red) and CD68 (green). E: Renal NF-κB p65 subunit mRNA expression by quantitative real-time PCR and NF-κB activation determined by DNA binding assay. F: Nox-2 and p22-phox mRNA expression in kidney determined by quantitative real-time PCR. Oxidative carbonylation of proteins in kidney homogenate was measured by ELISA. *P < 0.05 vs. CON; **P < 0.05 vs. STZ (n = 6 mice per group). (A high-quality digital representation of this figure is available in the online issue.)

Mentions: In diabetic DBA/2J mice, INT-747 treatment blocked the increase of TGF-β expression in diabetic kidneys, suggesting that FXR activation may counteract kidney fibrosis induced by TGF-β (Fig. 5A). In addition, INT-747 treatment markedly inhibited fibronectin expression in glomeruli (Fig. 5B) and significantly reduced renal α-SMA and FSP-1 expression, which were both increased in diabetic DBA/2J mice (Fig. 5C). FXR activation markedly decreased the expression of macrophage marker CD68 in the glomeruli of diabetic kidneys (Fig. 5D), which was consistent with its inhibition in p65 expression and NFκB activity (Fig. 5E). INT-747 also modulated oxidative stress, as shown by decreased NADPH oxidase Nox-2 and p22-phox expression and total protein carbonylation in diabetic kidneys from INT-747-treated mice (Fig. 5F).


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)

INT-747 treatment showed antifibrotic, anti-inflammatory, and antioxidative effects on diabetic DBA/2J mice. A: Renal TGF-β1 mRNA expression determined by quantitative real-time PCR. B: Immunofluorescence staining of kidney sections for fibronectin. The expression level of fibronectin was normalized to that in the control group. C: Expression of α-SMA in kidney determined by quantitative real-time PCR and immunohistologic staining. FSP-1 mRNA expression in kidney was determined by quantitative real-time PCR. D: Immunofluorescence staining of kidney sections for synaptopodin (red) and CD68 (green). E: Renal NF-κB p65 subunit mRNA expression by quantitative real-time PCR and NF-κB activation determined by DNA binding assay. F: Nox-2 and p22-phox mRNA expression in kidney determined by quantitative real-time PCR. Oxidative carbonylation of proteins in kidney homogenate was measured by ELISA. *P < 0.05 vs. CON; **P < 0.05 vs. STZ (n = 6 mice per group). (A high-quality digital representation of this figure is available in the online issue.)
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Related In: Results  -  Collection

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Figure 5: INT-747 treatment showed antifibrotic, anti-inflammatory, and antioxidative effects on diabetic DBA/2J mice. A: Renal TGF-β1 mRNA expression determined by quantitative real-time PCR. B: Immunofluorescence staining of kidney sections for fibronectin. The expression level of fibronectin was normalized to that in the control group. C: Expression of α-SMA in kidney determined by quantitative real-time PCR and immunohistologic staining. FSP-1 mRNA expression in kidney was determined by quantitative real-time PCR. D: Immunofluorescence staining of kidney sections for synaptopodin (red) and CD68 (green). E: Renal NF-κB p65 subunit mRNA expression by quantitative real-time PCR and NF-κB activation determined by DNA binding assay. F: Nox-2 and p22-phox mRNA expression in kidney determined by quantitative real-time PCR. Oxidative carbonylation of proteins in kidney homogenate was measured by ELISA. *P < 0.05 vs. CON; **P < 0.05 vs. STZ (n = 6 mice per group). (A high-quality digital representation of this figure is available in the online issue.)
Mentions: In diabetic DBA/2J mice, INT-747 treatment blocked the increase of TGF-β expression in diabetic kidneys, suggesting that FXR activation may counteract kidney fibrosis induced by TGF-β (Fig. 5A). In addition, INT-747 treatment markedly inhibited fibronectin expression in glomeruli (Fig. 5B) and significantly reduced renal α-SMA and FSP-1 expression, which were both increased in diabetic DBA/2J mice (Fig. 5C). FXR activation markedly decreased the expression of macrophage marker CD68 in the glomeruli of diabetic kidneys (Fig. 5D), which was consistent with its inhibition in p65 expression and NFκB activity (Fig. 5E). INT-747 also modulated oxidative stress, as shown by decreased NADPH oxidase Nox-2 and p22-phox expression and total protein carbonylation in diabetic kidneys from INT-747-treated mice (Fig. 5F).

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