Rapid development of glomerular injury and renal failure in mice lacking p53R2.
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.
Powell
David R
DR
Lexicon Genetics Incorporated, The Woodlands, TX 77381, USA. dpowell@lexgen.com
Desai
Urvi
U
Sparks
Mary Jean
MJ
Hansen
Gwenn
G
Gay
Jason
J
Schrick
Jeff
J
Shi
Zheng-Zheng
ZZ
Hicks
John
J
Vogel
Peter
P
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
D018797:Cell Cycle Proteins; D012264:Ribonucleotide Reductases; C486561:Rrm2b protein, mouse; C108427:ribonucleotide reductase R2 subunit
Obes Res. 2004 Jan;12(1):150-60
14742854
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14109-14
14610273
Curr Opin Pharmacol. 2003 Oct;3(5):563-70
14559104
Semin Nephrol. 1996 May;16(3):151-9
8734458
Curr Opin Biotechnol. 2001 Dec;12(6):626-31
11849946
Nat Genet. 2000 Apr;24(4):349-54
10742096
Nature. 1998 Apr 9;392(6676):608-11
9560157
Mol Cell Biol. 2001 Jul;21(14):4829-36
11416156
Nat Genet. 2000 Mar;24(3):251-6
10700177
J Am Soc Nephrol. 1999 Nov;10(11):2440-5
10541305
Nephrol Dial Transplant. 2004 May;19(5):1036-40
15004256
J Cell Sci. 1995 Jun;108 ( Pt 6):2369-79
7673356
Biotechniques. 1999 Jun;26(6):1150-6, 1158, 1160
10376154
J Virol. 1989 May;63(5):1924-8
2704070
Trends Biotechnol. 2002 Jan;20(1):36-42
11742676
Nat Genet. 2003 Aug;34(4):440-5
12858174
J Am Soc Nephrol. 2004 Mar;15(3):566-74
14978158
J Clin Invest. 2003 Mar;111(5):707-16
12618525
J Biol Chem. 2001 Nov 2;276(44):40647-51
11517226
J Cell Biol. 1999 Jun 14;145(6):1189-98
10366592
Nat Rev Drug Discov. 2003 Jan;2(1):38-51
12509758
PLoS Biol. 2004 Jun;2(6):e167
15208719
Nature. 2000 Mar 2;404(6773):42-9
10716435
Mol Biol Cell. 2004 Aug;15(8):3615-30
15155804
Curr Opin Nephrol Hypertens. 2004 Jan;13(1):9-15
15090854
J Am Soc Nephrol. 1995 Apr;5(10):1731-9
7787139
Pediatr Nephrol. 2003 Jan;18(1):3-8
12488982
Am J Kidney Dis. 2004 Feb;43(2):368-82
14750104