Role of the E2F1-p19-p53 pathway in ischemic acute renal failure.
BACKGROUND
Cell cycle progression and arrest of renal tubular cells after acute injury is a reactive process of renal regeneration. The p16(INK4a)/p19(ARF) (alternative reading frame) locus encodes two proteins involved in cell cycle regulation. We investigated the transcriptional regulation and tissue distribution of p19(ARF) in ischemic acute renal failure (ARF).


METHODS
We examined the time course and immunohistochemistry of p19(ARF) in rat kidneys following the induction of ischemic ARF. We also examined the effect of p19(ARF) overexpression on p53 levels and cell cycle progression in MDCK cells.


RESULTS
The protein expression of p19(ARF) strongly increased 72 h after the ischemia. Immunohistochemical studies showed that the renal tubular cells in the outer medulla expressed p19(ARF) protein 72 h after ischemic injury. The time course of E2F1 induction was observed at 6-24 h, and it was found to precede p19(ARF) expression. In MDCK cells, the overexpression of E2F1 increased promoter activity and the protein level of p19(ARF) and induced apoptosis. Transfection of the p19(ARF) expression vector caused an increase in p53 protein, cell cycle arrest and apoptosis.


CONCLUSIONS
These data support the hypothesis that the E2F1-p19(ARF)-p53 pathway forms a negative feedback loop to regulate the cell cycle of renal tubular cells in the ischemic ARF.
Tanaka
Hiroyuki
H
Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan.
Terada
Yoshio
Y
Okado
Tomokazu
T
Inoshita
Seiji
S
Kuwahara
Michio
M
Sasaki
Sei
S
D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014018:Tissue Distribution; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018797:Cell Cycle Proteins; D050687:E2F1 Transcription Factor; C493755:E2f1 protein, rat; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C508715:p19(ARF) protein, rat