Characterization of the renal phenotype in a mouse model of Marfan syndrome

Hartner, Andrea; Eifert, Timo; Haas, Christian; Tuysuz, Cigdem; Hilgers, Karl F.; Reinhardt, Dieter P.; Amann, Kerstin

doi:10.1007/s00428-004-1081-6

Cited by 14 publications

(15 citation statements)

References 26 publications

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“…The cross-sectional area of the glomerular tuft (AG) was determined from outlines of the tuft using the program Adobe Photoshop 7.0. Glomerular volume (VG) was calculated from the cross-sectional area with the formula VG ϭ ␤/ (AG) 3/2 where ␤ ϭ 1.38 is the shape coefficient for a sphere and ϭ 1.1 is the size distribution coefficient (13,14). The mesangial area (AM) within the glomerular tuft was defined as the area that stained positively for PAS (15)(16)(17)(18).…”

Section: Resarch Design and Methodsmentioning

confidence: 99%

Development of Late-Stage Diabetic Nephropathy in OVE26 Diabetic Mice

et al. 2004

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OVE26 mice are a transgenic model of severe earlyonset type 1 diabetes. These mice develop diabetes within the first weeks of life and can survive well over a year with no insulin treatment, and they maintain near normal body weight. To determine whether OVE26 mice provide a valuable model of chronic diabetic nephropathy (DN), OVE26 diabetic mice were compared with their nondiabetic littermates for functional and structural characteristics of DN. OVE26 mice exhibited pronounced polyuria and significant albuminuria by 2 months of age (305 g/24 h in OVE26 vs. 20 g/24 h in controls). Albumin excretion rate increased progressively with age and exceeded 15,000 g/24 h at 9 months of age. The profound loss of albumin led to hypoalbuminemia in some diabetic animals. Albuminuria coincided with an elevation in blood pressure as measured by tail cuff. The glomerular filtration rate (GFR) in OVE26 mice measured using fluorescein isothiocynate inulin clearance demonstrated that GFR increased significantly from 2 to 3 months of age and then decreased significantly from 5 to 9 months. GFR in 9-month-old diabetic mice was significantly lower than that of 9-month-old control mice. The decline in GFR coincided with a significant increase in renal vascular resistance. Structural studies showed an almost twofold increase in kidney weight between 2 and 5 months. Diabetic mice also showed progressively enlarged glomeruli and expanded mesangium with diffuse and nodular expansion of mesangial matrix. Tubulointerstitial fibrosis was also observed in these mice. Glomerular basement membrane was thickened in OVE26 mice. In summary, OVE26 mice demonstrate that most of the characteristics of human DN can be produced by chronic hyperglycemia in a murine model. This model will be useful for improved understanding and treatment of DN. A variety of experimentally induced or spontaneously hyperglycemic animals are used as models of human diabetes, such as streptoztocin-induced diabetic rats, NOD mice, and db/db mice. The kidney disease in many of these animals has been characterized (2,3), but none display the full array of features characteristic of human DN. In fact, the current mouse models primarily display features consistent with the earliest phase of DN, such as microalbuminuria (4,5). This is not surprising since these mouse models typically suffer from diabetes for several months, while the complete pattern of human DN requires decades to develop.In the current article, we follow the development of DN in a transgenic model of insulinopenic diabetes, the OVE26 mouse (6). The advantages of this model for the study of complications are straightforward: direct damage is limited to the ␤-cell, diabetes develops early, and very severe diabetes lasts for Ͼ1 year. Our results show that with respect to albuminuria, mesangial matrix accumulation, glomerular filtration rate (GFR), and interstitial fibrosis, OVE26 mice are significantly closer to advanced human DN than other available mouse models. RESARCH DESIGN AND METHODSOVE26 mice on the FVB ba...

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Section: Resarch Design and Methodsmentioning

confidence: 99%

Development of Late-Stage Diabetic Nephropathy in OVE26 Diabetic Mice

et al. 2004

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“…The cross-sectional area of the glomerular tuft (AG) was determined from outlines of the tuft using the program Adobe Photoshop 7.0. Glomerular volume (VG) was calculated from the cross-sectional area using the formula VG0b/k (AG)3/2, where b0 1.38 is the shape coefficient for a sphere and k01.1 is the size distribution coefficient [22,23].…”

Section: Histopathological Studiesmentioning

confidence: 99%

Metallothionein over-expression in podocytes reduces adriamycin nephrotoxicity

Yang

Zheng

Epstein

2009

Free Radical Research

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Adriamycin (ADR) is nephrotoxic. One component of ADR-induced nephropathy may be oxidative stress. This study used a recently developed line of transgenic mice (Nmt) on the FVB background strain, which over-express the antioxidant protein metallothionein (MT) in podocytes. Cultured podocytes from Nmt mice were resistant to H(2)O(2) injury, as judged by disruption of F-actin filaments. FVB control and transgenic mice received 11 mg/kg body weight ADR by tail vein injection and 24-h urine samples were then collected for albumin analysis. Also renal morphology was investigated by light and electron microscopy. Urine albumin analysis showed that ADR treatment significantly increased albuminuria in control mice, indicating that the FVB strain is sensitive to ADR nephropathy and Nmt mice were significantly protected from elevated albuminuria. Glomerular histopathology revealed that ADR reduced podocyte number and produced foot process effacement in FVB mice. The Nmt transgene protected podocyte numbers and podocyte foot processes from the effects of ADR. These results show that metallothionein can protect podocytes from ADR toxicity.

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“…All animals were genotyped with polymerase chain reaction as described. 26 At 2 and 4 months after birth, the mice were killed and the ascending aortas were prepared. Aortic tissue extracts were prepared using a modification of a previously described protocol.…”

Section: Preparation Of Murine Aortic Extractsmentioning

confidence: 99%

Induction of Macrophage Chemotaxis by Aortic Extracts of the mgR Marfan Mouse Model and a GxxPG-Containing Fibrillin-1 Fragment

et al. 2006

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Background-The primary cause of early death in untreated Marfan syndrome (MFS) patients is aortic dilatation and dissection. Methods and Results-We investigated whether ascending aortic samples from the fibrillin-1-underexpressing mgR mouse model for MFS or a recombinant fibrillin-1 fragment containing an elastin-binding protein (EBP) recognition sequence can act as chemotactic stimuli for macrophages. Both the aortic extracts from the mgR/mgR mice and the fibrillin-1 fragment significantly increased macrophage chemotaxis compared with extracts from wild-type mice or buffer controls. The chemotactic response was significantly diminished by pretreatment of macrophages with lactose or with the elastin-derived peptide VGVAPG and by pretreatment of samples with a monoclonal antibody directed against an EBP recognition sequence. Mutation of the EBP recognition sequence in the fibrillin-1 fragment also abolished the chemotactic response. These results indicate the involvement of EBP in mediating the effects. Additionally, investigation of macrophages in aortic specimens of MFS patients demonstrated macrophage infiltration in the tunica media. Conclusions-Our findings demonstrate that aortic extracts from mgR/mgR mice can stimulate macrophage chemotaxis by interaction with EBP and show that a fibrillin-1 fragment possesses chemotactic stimulatory activity similar to that of elastin degradation peptides. They provide a plausible molecular mechanism for the inflammatory infiltrates observed in the mgR mouse model and suggest that inflammation may represent a component of the complex pathogenesis of

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Characterization of the renal phenotype in a mouse model of Marfan syndrome

Cited by 14 publications

References 26 publications

Development of Late-Stage Diabetic Nephropathy in OVE26 Diabetic Mice

Development of Late-Stage Diabetic Nephropathy in OVE26 Diabetic Mice

Metallothionein over-expression in podocytes reduces adriamycin nephrotoxicity

Induction of Macrophage Chemotaxis by Aortic Extracts of the mgR Marfan Mouse Model and a GxxPG-Containing Fibrillin-1 Fragment

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