SFEBES2009 Poster Presentations Bone (25 abstracts)
A mouse model of early-onset renal failure, tertiary hyperparathyroidism and renal osteodystrophy
Chris Esapa 1, , Rosie Head 1, , Simona Di Pretoro 1, , Elisabeth Crane 1, , Nellie Loh 1 , Olivier Devuyst 3 , Gethin Thomas 4 , Steve Brown 2 , Matt Brown 1, , Peter Croucher 5 , Roger Cox 2 & Rajesh Thakker 1
1University of Oxford, Oxford, UK; 2MRC Harwell, Harwell, UK; 3Louvain Medical School, Brussels, Belgium; 4University of Queensland, Woolloongabba, Queensland, Australia; 5University of Sheffield, Sheffield, UK.
Abnormalities of calcium homeostasis such as secondary or tertiary hyperparathyroidism, and renal osteodystrophy often occur in patients with kidney failure. However, investigations of the underlying molecular mechanisms have been hampered by the lack of available tissues from patients and the lack of suitable animal models. We therefore sought to overcome this limitation by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea and identified a mouse model with renal failure designated renf. Mice were kept in accordance with national welfare guidelines and project license restrictions. Renf mice were found to be smaller than their littermates at weaning, failed to thrive and did not live beyond the age of 8 weeks. Renf mice had kidneys that were smaller and irregularly shaped. Histological analysis using haematoxylin and eosin stained sections revealed focal enlargements of tubular epithelial cells, interstitial damage, and concretions in the lumen of tubules which also stained positive for periodic-acid Schiff. TUNEL analysis of renf kidney sections showed increased apoptosis that predominantly affected the tubules. These features are consistent with tubulointerstitial nephritis. Analysis of plasma samples from renf mice revealed elevated concentrations of urea, creatinine, phosphate, calcium and alkaline phosphatase consistent with tertiary hyperparathyroidism and renal osteodystrophy. Inheritance testing demonstrated that renf was transmitted as an autosomal recessive disorder and genetic studies using DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the renf locus to a 9.3 Mb region on chromosome 17. Thus, we have established a novel mouse model for autosomal recessive tubulointerstitial nephritis and early-onset renal failure that results in tertiary hyperparathyroidism and renal osteodystrophy. This mouse model will help to increase our understanding of the molecular mechanisms associated with end-stage renal disease.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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