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Induction of Zf9 in the kidney following early ischemia/reperfusion
Ridwan Tarabishi1, Kamyar Zahedi, Jaya Mishra
1Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.
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.
Conclusion:
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.
Insights
Early cell injury in acute renal failure (ARF) is better understood by studying Zf9 and transforming growth factor-beta1 (TGF-beta1) induction. These factors play a key role in the early apoptotic response to ischemic renal injury.
Area of Science:
- Nephrology
- Molecular Biology
- Cellular Injury Mechanisms
Background:
- Understanding early cell injury mechanisms is crucial for treating acute renal failure (ARF).
- Identifying early molecular events in ARF pathogenesis can reveal novel therapeutic targets.
Purpose of the Study:
- To identify renal genes rapidly induced after ischemia in a mouse model.
- To investigate the role of these genes in the pathogenesis of acute renal failure.
Main Methods:
- Utilized cDNA microarrays to screen for early-response genes post-renal ischemia.
- Confirmed gene and protein expression using Northern, Western blot, and knockdown analyses.
- Investigated gene and protein responses in cultured human proximal tubule cells under ischemic conditions.
Main Results:
- Zf9, a transcription factor regulating TGF-beta1, was the most highly induced gene (21-fold at 3 hours).
- Zf9 mRNA and protein, along with TGF-beta1 protein, showed rapid and parallel induction post-ischemia.
- Knockdown of Zf9 using antisense oligonucleotides reduced TGF-beta1 induction and inhibited apoptosis.
Conclusions:
- Zf9 and its transactivating factor TGF-beta1 are critically involved in the early apoptotic response to ischemic renal injury.
- This study highlights a previously unrecognized role for Zf9 and TGF-beta1 in ARF pathogenesis.
