Positive effect of the induction of p21WAF1/CIP1 on the course of ischemic acute renal failure.
BACKGROUND
The p21 protein is found in the nucleus of most cells where it modulates cell cycle activity. At low levels, p21 stabilizes interactions between D cyclins and their cyclin-dependent kinases (cdks), but at high levels after induction by several different stress pathways, it causes cell cycle arrest. The p21 mRNA is induced in murine kidney after several types of acute renal failure, including cisplatin administration, ischemia-reperfusion, and ureteral obstruction. We reported that after cisplatin injection, mice with a p21 gene deletion developed much more severe renal damage than wild-type mice. To dissociate the effects of cisplatin-induced DNA damage and subsequent initiation of DNA damage-dependent cell death pathways from effects of acute renal failure, we have now examined mice after ischemia-reperfusion, a model of renal failure not associated with genotoxin-induced DNA damage early after the injury.


METHODS
Wild-type and p21(-/-) mice were made ischemic by clamping both renal hila for 30 or 50 minutes. At various times after reflow, mortality and parameters of renal function and morphology were quantified. Also, the nuclear proteins p21 and proliferating cell nuclear antigen (PCNA) were localized in kidney sections by immunohistochemistry.


RESULTS
Kidney function was more impaired and mortality increased significantly in p21(-/-) mice as compared with p21(+/+) mice. We found more cell cycle activity, indicated by increased number of mitotic cells and nuclear PCNA-positive cells, in kidney of p21(-/-) mice.


CONCLUSIONS
In this study, p21(-/-) mice were more susceptible to ischemia-induced acute renal failure, with similarly elevated levels of parameters of cell cycle activity. We propose that the increased and inappropriate cell cycle activity in kidney cells is responsible for the increased kidney impairment and mortality.
Megyesi
J
J
Division of Nephrology, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Andrade
L
L
Vieira
J M
JM
Safirstein
R L
RL
Price
P M
PM
D058186:Acute Kidney Injury / Q000209:etiology* / Q000503:physiopathology*; D000818:Animals; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology*; D007511:Ischemia / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000473:pathology; D016019:Survival Analysis
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins