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Rapid development of glomerular injury and renal failure in mice lacking p53R2

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Abstract

The Rrm2b gene encodes p53R2, a catalytic subunit of ribonucleotide reductase that is required for DNA repair. Embryonic stem (ES) cells containing a retroviral insertion in the Rrm2b locus were used to generate mutant mice. Analysis of kidney RNA from Rrm2b (−/−) mice showed that the retroviral insertion disrupted expression of Rrm2b transcripts. Rrm2b (−/−) pups were represented at the expected Mendelian ratios at 10–12 days of age and grew normally past weaning. Mice failed to thrive after 6 weeks of age and began to die by 8 weeks of age. Phenotyping revealed that Rrm2b (−/−) mice died from a severe glomerular lesion that led to nephrotic syndrome and chronic renal failure. In kidneys of Rrm2b (−/−) mice, podocytes were enlarged and there was evidence of foot process effacement by 6 weeks of age. By 8 weeks of age, progressive podocyte hypertrophy and loss of foot processes was accompanied by hypertrophy of glomerular capillary endothelial cells that was extensive enough to restrict capillary blood flow. Collapsing glomerulopathy with avascular glomeruli was widespread in mice surviving beyond 9 weeks of age. Additional abnormalities in other organ systems were minor or consistent with secondary effects of renal failure. These findings suggest that lack of p53R2, the protein encoded by Rrm2b, has early and relatively selective detrimental effects on the kidney glomerulus that lead to rapid death from progressive renal failure.

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Acknowledgements

We thank Elizabeth Wilson for immunohistochemistry and Kathy Troughton for electron microscopy support, and Carol Jones for obtaining the urinalysis data.

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Authors and Affiliations

  1. Lexicon Genetics Incorporated, The Woodlands, TX 77381, USA

    David R. Powell, Urvi Desai, Mary Jean Sparks, Gwenn Hansen, Jason Gay, Jeff Schrick, Zheng-Zheng Shi & Peter Vogel

  2. Department of Pathology, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX 77030, USA

    John Hicks

  3. Department of Endocrinology, Pharmaceutical Biology, Lexicon Genetics Incorporated, 8800 Technology Forest Place, The Woodlands, TX 77381-1160, USA

    David R. Powell

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  1. David R. Powell
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  2. Urvi Desai
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Correspondence to David R. Powell.

Additional information

This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany

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Powell, D.R., Desai, U., Sparks, M.J. et al. Rapid development of glomerular injury and renal failure in mice lacking p53R2. Pediatr Nephrol 20, 432–440 (2005). https://doi.org/10.1007/s00467-004-1696-5

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  • DOI: https://doi.org/10.1007/s00467-004-1696-5

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