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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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Renal histopathology in diabetic FXR KO mice. A–I: Representative PAS staining of kidney sections: nondiabetic wild-type C57BL/6, WT (A); diabetic wild-type C57BL/6, WT/STZ (B); nondiabetic FXR KO, KO (C); diabetic FXR KO, KO/STZ (D–H). A–G: Glomerular histopathology. Diabetic FXR KO mice exhibited patent foam cell accumulation (D–G) with dilated capillaries (E) or ballooning of capillaries (F and G). H: Tubulointerstitial injury shown by dilated tubules with flattened epithelium and lipid droplets. I: Mesangial expansion index defined by the ratio of mesangial area/glomerular tuft area. The mesangial area is determined by assessment of PAS-positive and nucleus-free areas in the mesangium excluding glomeruli that accompany mesangiolysis or foam cells. *P < 0.05 as specified (n = 6 mice per group). J–M: Representative Masson's trichrome staining of kidney sections showing the tubulointerstitial fibrosis in diabetic FXR KO mice. N–R: Electron micrographs of glomeruli showing reactive podocyte and endothelial cell (Q) and lytic mesangium (R) in diabetic FXR KO mice. Irregular thickening of GBM in Q indicates possible subepithelial deposit and increased vesicles in the podocyte cell body. Arrows in Q show effacement of podocyte foot processes. Lytic leision in R looks like lipid deposits or cholesterol “clefts.” Scale bar: A–G, 50 μm (shown in G); H, 50 μm; J–M, 50 μm (shown in M); N–Q, 2 μm; R, 10 μm. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 1: Renal histopathology in diabetic FXR KO mice. A–I: Representative PAS staining of kidney sections: nondiabetic wild-type C57BL/6, WT (A); diabetic wild-type C57BL/6, WT/STZ (B); nondiabetic FXR KO, KO (C); diabetic FXR KO, KO/STZ (D–H). A–G: Glomerular histopathology. Diabetic FXR KO mice exhibited patent foam cell accumulation (D–G) with dilated capillaries (E) or ballooning of capillaries (F and G). H: Tubulointerstitial injury shown by dilated tubules with flattened epithelium and lipid droplets. I: Mesangial expansion index defined by the ratio of mesangial area/glomerular tuft area. The mesangial area is determined by assessment of PAS-positive and nucleus-free areas in the mesangium excluding glomeruli that accompany mesangiolysis or foam cells. *P < 0.05 as specified (n = 6 mice per group). J–M: Representative Masson's trichrome staining of kidney sections showing the tubulointerstitial fibrosis in diabetic FXR KO mice. N–R: Electron micrographs of glomeruli showing reactive podocyte and endothelial cell (Q) and lytic mesangium (R) in diabetic FXR KO mice. Irregular thickening of GBM in Q indicates possible subepithelial deposit and increased vesicles in the podocyte cell body. Arrows in Q show effacement of podocyte foot processes. Lytic leision in R looks like lipid deposits or cholesterol “clefts.” Scale bar: A–G, 50 μm (shown in G); H, 50 μm; J–M, 50 μm (shown in M); N–Q, 2 μm; R, 10 μm. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: Wild-type C57BL/6 mice or nondiabetic FXR KO mice showed nearly normal glomerular structure with only mild mesangial expansion (Fig. 1A–C). In contrast, the glomerular tufts in diabetic FXR KO mice exhibited foam cell accumulation with glomerular lobulation enlarging the entire glomerular area and more mesangial matrix expansion (Fig. 1D–I). Some capillaries were extended and occluded by foam cells or dilated and contained pale-staining material (Fig. 1E). Some glomeruli displayed prominent mesangiolysis accompanied by ballooning of capillaries (Fig. 1F and G). In tubulointerstitial areas, wild-type mice or nondiabetic FXR KO mice showed no significant tubular damage, whereas diabetic FXR KO mice had remarkable tubulointerstitial changes. The tubules were dilated, lined by flattened epithelium, and contained proteinaceous casts with large amounts of lipid droplets deposited in the tubular epithelial cells (Fig. 1H). Interstitial collagen deposition was studied in Masson's trichrome-stained renal sections as an index of interstitial fibrosis. Diabetic FXR KO mice showed more interstitial fibrosis than wild-type mice and nondiabetic FXR KO mice (Fig. 1J–M).


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)

Renal histopathology in diabetic FXR KO mice. A–I: Representative PAS staining of kidney sections: nondiabetic wild-type C57BL/6, WT (A); diabetic wild-type C57BL/6, WT/STZ (B); nondiabetic FXR KO, KO (C); diabetic FXR KO, KO/STZ (D–H). A–G: Glomerular histopathology. Diabetic FXR KO mice exhibited patent foam cell accumulation (D–G) with dilated capillaries (E) or ballooning of capillaries (F and G). H: Tubulointerstitial injury shown by dilated tubules with flattened epithelium and lipid droplets. I: Mesangial expansion index defined by the ratio of mesangial area/glomerular tuft area. The mesangial area is determined by assessment of PAS-positive and nucleus-free areas in the mesangium excluding glomeruli that accompany mesangiolysis or foam cells. *P < 0.05 as specified (n = 6 mice per group). J–M: Representative Masson's trichrome staining of kidney sections showing the tubulointerstitial fibrosis in diabetic FXR KO mice. N–R: Electron micrographs of glomeruli showing reactive podocyte and endothelial cell (Q) and lytic mesangium (R) in diabetic FXR KO mice. Irregular thickening of GBM in Q indicates possible subepithelial deposit and increased vesicles in the podocyte cell body. Arrows in Q show effacement of podocyte foot processes. Lytic leision in R looks like lipid deposits or cholesterol “clefts.” Scale bar: A–G, 50 μm (shown in G); H, 50 μm; J–M, 50 μm (shown in M); N–Q, 2 μm; R, 10 μm. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 1: Renal histopathology in diabetic FXR KO mice. A–I: Representative PAS staining of kidney sections: nondiabetic wild-type C57BL/6, WT (A); diabetic wild-type C57BL/6, WT/STZ (B); nondiabetic FXR KO, KO (C); diabetic FXR KO, KO/STZ (D–H). A–G: Glomerular histopathology. Diabetic FXR KO mice exhibited patent foam cell accumulation (D–G) with dilated capillaries (E) or ballooning of capillaries (F and G). H: Tubulointerstitial injury shown by dilated tubules with flattened epithelium and lipid droplets. I: Mesangial expansion index defined by the ratio of mesangial area/glomerular tuft area. The mesangial area is determined by assessment of PAS-positive and nucleus-free areas in the mesangium excluding glomeruli that accompany mesangiolysis or foam cells. *P < 0.05 as specified (n = 6 mice per group). J–M: Representative Masson's trichrome staining of kidney sections showing the tubulointerstitial fibrosis in diabetic FXR KO mice. N–R: Electron micrographs of glomeruli showing reactive podocyte and endothelial cell (Q) and lytic mesangium (R) in diabetic FXR KO mice. Irregular thickening of GBM in Q indicates possible subepithelial deposit and increased vesicles in the podocyte cell body. Arrows in Q show effacement of podocyte foot processes. Lytic leision in R looks like lipid deposits or cholesterol “clefts.” Scale bar: A–G, 50 μm (shown in G); H, 50 μm; J–M, 50 μm (shown in M); N–Q, 2 μm; R, 10 μm. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: Wild-type C57BL/6 mice or nondiabetic FXR KO mice showed nearly normal glomerular structure with only mild mesangial expansion (Fig. 1A–C). In contrast, the glomerular tufts in diabetic FXR KO mice exhibited foam cell accumulation with glomerular lobulation enlarging the entire glomerular area and more mesangial matrix expansion (Fig. 1D–I). Some capillaries were extended and occluded by foam cells or dilated and contained pale-staining material (Fig. 1E). Some glomeruli displayed prominent mesangiolysis accompanied by ballooning of capillaries (Fig. 1F and G). In tubulointerstitial areas, wild-type mice or nondiabetic FXR KO mice showed no significant tubular damage, whereas diabetic FXR KO mice had remarkable tubulointerstitial changes. The tubules were dilated, lined by flattened epithelium, and contained proteinaceous casts with large amounts of lipid droplets deposited in the tubular epithelial cells (Fig. 1H). Interstitial collagen deposition was studied in Masson's trichrome-stained renal sections as an index of interstitial fibrosis. Diabetic FXR KO mice showed more interstitial fibrosis than wild-type mice and nondiabetic FXR KO mice (Fig. 1J–M).

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