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1 Department of Pediatrics, Children Hospital Medical Center, Cincinnati, OH, USA
2 Division of Nephrology and Hypertension, Department of Medicine, University of Cincinnati, Cincinnati, OH, USA
3 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
4 Rosewell Park Center Institute, Buffalo, NY, USA
5 Division of Nephrology and Hypertension, Department of Medicine, University of Cincinnati, Cincinnati, OH, USA; Veterans Affairs Medical Center, Cincinnati, OH, USA
* To whom correspondence should be addressed. E-mail: manoocher.soleimani{at}uc.edu.
Ischemia/reperfusion injury (IRI) is the major cause of acute renal failure (ARF) in both native and allograft kidneys. Identifying the molecules and pathways involved in the pathophysiology of renal IRI will yield valuable new diagnostic and therapeutic information. To identify differentially regulated genes in renal IRI, RNA from rat kidneys subjected to an established renal IRI protocol (bilateral occlusion of renal pedicles for 30 min followed by reperfusion) and time-matched kidneys from sham-operated animals - were subjected to Suppression Subtractive Hybridization (SSH). The level of Spermidine/Spermine N-1 Acetyl Transferase (SSAT) mRNA, an essential enzyme for the catabolism of polyamines, increased in renal IRI. SSAT expression was found throughout normal kidney tubules, as detected by nephron segment RT-PCR. Northern blots demonstrated that the mRNA levels of SSAT are increased by greater than 3-fold in the renal cortex and by 5-fold in the renal medulla at 12 hrs and returned to baseline at 48 hrs of postischemia. The increase in SSAT mRNA was paralleled by an increase in SSAT protein levels as determined by western blot analysis. The concentration of putrescine in the kidney increased by ~4 and ~7.5 fold at 12 and 24 hrs of reperfusion, respectively, consistent with increased functional activity of SSAT. To assess the specificity of SSAT for tubular injury, a model of acute renal failure from sodium depletion (without tubular injury) was studied; SSAT mRNA levels remained unchanged in rats subjected to sodium depletion. As evidence to distinguish SSAT increases from the effects of tubular injury versus uremic toxins, SSAT was increased in cis-platinum treated animals before the onset of renal failure. The expression of SSAT mRNA and protein increased by ~ 3.5 fold and > 10 fold, respectively, in renal tubule epithelial cells subjected to ATP depletion and metabolic poisoning (an in vitro model of kidney IRI). Our results suggest that SSAT is likely a new marker of tubular cell injury that distinguishes pre-renal from intra-renal ARF.
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