title: Rapid development of glomerular injury and renal failure in mice lacking p53R2.
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.
authors.affiliation: Lexicon Genetics Incorporated, The Woodlands, TX 77381, USA. dpowell@lexgen.com
authors.forename: David R
authors.initials: DR
authors.lastname: Powell
authors.forename: Urvi
authors.initials: U
authors.lastname: Desai
authors.forename: Mary Jean
authors.initials: MJ
authors.lastname: Sparks
authors.forename: Gwenn
authors.initials: G
authors.lastname: Hansen
authors.forename: Jason
authors.initials: J
authors.lastname: Gay
authors.forename: Jeff
authors.initials: J
authors.lastname: Schrick
authors.forename: Zheng-Zheng
authors.initials: ZZ
authors.lastname: Shi
authors.forename: John
authors.initials: J
authors.lastname: Hicks
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D005260:Female; D007678:Kidney Glomerulus / Q000473:pathology*; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D051437:Renal Insufficiency / Q000235:genetics* / Q000473:pathology*; D012264:Ribonucleotide Reductases / Q000235:genetics*; D013997:Time Factors
chemical_list: D018797:Cell Cycle Proteins; D012264:Ribonucleotide Reductases; C486561:Rrm2b protein, mouse; C108427:ribonucleotide reductase R2 subunit
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