Induction of Zf9 in the kidney following early ischemia/reperfusion.
BACKGROUND
An improved understanding of the early cell injury mechanisms is critical for effective therapy of acute renal failure (ARF).


METHODS
We utilized cDNA microarrays to identify renal genes that are induced very early after renal ischemia in a mouse model, whose protein products might provide novel information regarding the pathogenesis of ARF. The findings were confirmed by downstream mRNA and protein expression studies, as well as knockdown analysis with antisense primers.


RESULTS
The maximally induced gene (21-fold at 3 hours of reflow) was Zf9, a Kruppel-like transcription factor involved in the regulation of transforming growth factor-beta1 (TGF-beta1). The rapid induction of Zf9 mRNA was confirmed by Northern analysis (14.5-fold at 3 hours of reflow) and that of Zf9 protein by Western analysis (10.5-fold at 3 hours of reflow). Zf9 protein was induced in both proximal and distal tubule cells in a cytoplasmic as well as nuclear distribution. TGF-beta1 protein was also up-regulated in a pattern parallel to that of Zf9. In cultured human proximal tubule cells, induction of ischemia by partial adenosine triphosphate (ATP) depletion resulted in a rapid up-regulation of both Zf9 and of TGF-beta1 proteins. Antisense oligonucleotides to Zf9 markedly blunted the induction of Zf9 and TGF-beta1, and significantly inhibited the apoptotic response to ATP depletion.


CONCLUSIONS
Induction of Zf9 and its transactivating factor TGF-beta1 may play a critical and hitherto unrecognized role in the early apoptotic response to ischemic renal injury.
Tarabishi
Ridwan
R
Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.
Zahedi
Kamyar
K
Mishra
Jaya
J
Ma
Qing
Q
Kelly
Caitlin
C
Tehrani
Kathy
K
Devarajan
Prasad
P
D058186:Acute Kidney Injury / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016375:Antisense Elements (Genetics); D017209:Apoptosis / Q000502:physiology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007668:Kidney / Q000473:pathology / Q000502:physiology*; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D015427:Reperfusion Injury / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D016375:Antisense Elements (Genetics); C491358:Klf6 protein, mouse; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000255:Adenosine Triphosphate