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

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

Research output: Contribution to journalArticle

27 Scopus citations

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 dis upted 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.

Original languageEnglish (US)
Pages (from-to)432-440
Number of pages9
JournalPediatric Nephrology
Volume20
Issue number3 SPEC. ISS.
DOIs
StatePublished - Mar 2005

Keywords

  • Gene trap
  • Glomerulopathy
  • Knockout
  • Nephrotic syndrome
  • Podocyte

ASJC Scopus subject areas

  • Nephrology
  • Pediatrics, Perinatology, and Child Health

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