Role of p53-dependent activation of caspases in chronic obstructive uropathy: evidence from p53 null mutant mice.
Chronic obstructive uropathy (COU) created by unilateral ureteric ligation is associated with increased renal cell apoptosis and p53 expression. Genetically engineered mice were used to examine the role of p53 in renal cell apoptosis in COU and the involved molecular pathways. Obstructed kidneys in p53+/+, p53+/-, and p53-/- mice were examined at days 4, 7, 15, 20, and 30 for apoptosis, and mRNA were examined for p53, members of the bcl-2 family, the death receptor family, and the common effectors of apoptosis. Obstructed kidneys in p53+/- and p53-/- mice exhibited equal attenuation of tubular and interstitial cell apoptosis (70 and 50%, respectively), compared with p53+/+ mice. However, p53 gene deficiency did not confer complete protection from apoptosis. Obstructed kidneys from p53-/- mice did not express p53 mRNA, whereas those from p53+/- and p53+/+ mice displayed mild and marked increase in their expression, respectively. Obstructed kidneys in p53+/+, p53+/-, and p53-/- mice displayed upregulation of mRNA for members of the bcl-2 family and most of the death receptor family, except for a lower level of tumor necrosis factor receptor-1, TRAIL, and FAP in p53+/+ mice. Obstructed kidneys in p53-/- and p53+/- mice showed virtual absence of caspase 11 and marked attenuation of caspases 1 and 12, contrasted with their strong expression in p53+/+ kidneys. These data suggest that apoptosis in obstructed kidneys involves p53-dependent as well as p53-independent pathways. The p53-dependent pathway may involve activation of caspases 1, 11, and 12, whereas the p53-independent pathway may involve activation of members of the bcl-2 and death receptor families.
Choi
Yeong-Jin
YJ
Renal Pathology Laboratory, Department of Pathology The Methodist Hospital Houston, Texas.
Mendoza
Leonardo
L
Department of Medicine, The Methodist Hospital Houston, Texas.
Rha
Suk-Joo
SJ
Renal Pathology Laboratory, Department of Pathology The Methodist Hospital Houston, Texas.
Sheikh-Hamad
David
D
Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas.
Baranowska-Daca
Elzbieta
E
Renal Pathology Laboratory, Department of Pathology The Methodist Hospital Houston, Texas.
Nguyen
Vinh
V
Renal Pathology Laboratory, Department of Pathology The Methodist Hospital Houston, Texas.
Smith
C Wayne
CW
Department of Medicine, The Methodist Hospital Houston, Texas.
Nassar
George
G
Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas.
Suki
Wadi N
WN
Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas.
Truong
Luan D
LD
Renal Pathology Laboratory, Department of Pathology The Methodist Hospital Houston, Texas.|Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas.
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D019254:Genes, bcl-2; D016158:Genes, p53; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014517:Ureteral Obstruction / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D020169:Caspases