Chronic kidney disease (CKD) is characterized by renal
fibrosis that can lead to
end-stage renal failure, and studies have supported a strong genetic influence on the risk of developing CKD. However, investigations of the underlying molecular mechanisms are hampered by the lack of suitable hereditary models in animals. We therefore sought to establish hereditary mouse models for CKD and renal
fibrosis by investigating mice treated with the chemical
mutagen N-ethyl-N-nitrosourea, and identified a mouse with autosomal recessive
renal failure, designated RENF. Three-week old RENF mice were smaller than their littermates, whereas at birth they had been of similar size. RENF mice, at 4-weeks of age, had elevated concentrations of plasma
urea and
creatinine, indicating
renal failure, which was associated with small and irregularly shaped kidneys. Genetic studies using
DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the Renf locus to a 5.8 Mbp region on chromosome 17E1.3.
DNA sequencing of the
xanthine dehydrogenase (Xdh) gene revealed a
nonsense mutation at
codon 26 that co-segregated with affected RENF mice. The Xdh mutation resulted in loss of hepatic XDH and renal
Cyclooxygenase-2 (COX-2) expression. XDH mutations in man cause xanthinuria with undetectable plasma
uric acid levels and three RENF mice had plasma
uric acid levels below the limit of detection. Histological analysis of RENF kidney sections revealed abnormal arrangement of glomeruli, intratubular casts, cellular infiltration in the interstitial space, and interstitial
fibrosis. TUNEL analysis of RENF kidney sections showed extensive apoptosis predominantly affecting the tubules. Thus, we have established a mouse model for autosomal recessive early-onset
renal failure due to a
nonsense mutation in Xdh that is a model for xanthinuria in man. This mouse model could help to increase our understanding of the molecular mechanisms associated with renal
fibrosis and the specific roles of XDH and
uric acid.