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Overexpression of SSAT in Kidney Cells Recapitulates Various Phenotypic Aspects of Kidney Ischemia-reperfusion Injury

Zhaohui Wang^*,, Kamyar Zahedi^,, Sharon Barone^*, Kathy Tehrani, Hamid Rabb, Karl Matlin^¶, Robert A. Casero^# and Manoocher Soleimani^*,||

*Division of Nephrology and Hypertension, Department of Medicine, University of Cincinnati, Division of Nephrology and Hypertension, Department of Pediatrics, Children Hospital Medical Center, and ^¶Department of Surgery, University of Cincinnati, Cincinnati, Ohio; Division of Nephrology and ^#Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; and ^||Veterans Affairs Medical Center, Cincinnati, Ohio.

Correspondence to Dr. Manoocher Soleimani, Division of Nephrology and Hypertension, Department of Medicine, University of Cincinnati, 231 Albert Sabin Way, MSB 259G, Cincinnati, OH 45267-0585. Phone: 513-558-5463; Fax: 513-558-4309; E-mail: Manoocher.soleimani{at}uc.edu

ABSTRACT. To ascertain the role of spermidine/spermine N-1-acetyl-transferase (SSAT; the rate-limiting enzyme in polyamine catabolism) in cell injury, cultured kidney (HEK 293) cells conditionally overexpressing SSAT were generated. The SSAT expression was induced and its enzymatic activity increased 24 h after addition of tetracycline and remained elevated over the length of the experiments. Induction of SSAT upregulated the expression of polyamine oxidase and resulted in the reduction of cellular concentration of spermidine and spermine, increased concentration of putrescine, and inhibited cell growth. SSAT overexpression increased the expression of heme oxygenase-1 (HO-1) by 350% 24 h after addition of tetracycline, indicating the induction of oxidative stress. The presence of catalase significantly prevented the upregulation of HO-1 in SSAT overexpressing cells, indicating that generation of H₂O₂ is partially responsible for the induction of oxidative stress. Overexpression of SSAT caused rounding and loss of cell anchorage and significantly altered the morphology of actin-containing filopodia, suggesting an adhesion defect. SSAT upregulation may mediate majority of the oxidative stress in kidney ischemia-reperfusion injury (IRI) as manifested by decreased cell growth, generation of toxic metabolites (H₂O₂ and putrescine), upregulation of HO-1, disruption of cell anchorage, and defect in cell adhesion. These data point to the inhibition of polyamine catabolism as a therapeutic approach for the prevention of tissue injury in kidney IRI.

This article has been cited by other articles:

				K. Zahedi, J. J. Bissler, Z. Wang, A. Josyula, L. Lu, P. Diegelman, N. Kisiel, C. W. Porter, and M. Soleimani Spermidine/spermine N1-acetyltransferase overexpression in kidney epithelial cells disrupts polyamine homeostasis, leads to DNA damage, and causes G2 arrest Am J Physiol Cell Physiol, March 1, 2007; 292(3): C1204 - C1215. [Abstract] [Full Text] [PDF]

				Y. Wang and R. A. Casero Jr. Mammalian Polyamine Catabolism: A Therapeutic Target, a Pathological Problem, or Both? J. Biochem., January 1, 2006; 139(1): 17 - 25. [Abstract] [Full Text] [PDF]

				S. Barone, T. Okaya, S. Rudich, S. Petrovic, K. Tenrani, Z. Wang, K. Zahedi, R. A. Casero, A. B. Lentsch, and M. Soleimani Distinct and sequential upregulation of genes regulating cell growth and cell cycle progression during hepatic ischemia-reperfusion injury Am J Physiol Cell Physiol, October 1, 2005; 289(4): C826 - C835. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673