Polyamine metabolism in heart and kidney ischemic injury

Summary

Principal Investigator: M Soleimani
Abstract: Conditions associated with ischemia/reperfusion injury (IRI) such as myocardial infarction and acute ischemic renal failure are among the major causes of morbidity and mortality. The pathophysiology of IRI is strikingly similar in heart and kidney, with enhanced production of toxic metabolites (i.e. H202), increased apoptosis, and cell death following reperfusion, raising the possibility that identical pathway(s) may mediate cell injury and dysfunction in both organs in IRI. In an attempt to identify the factors involved in the pathophysiology of IRI, suppression subtractive hybridization on RNA from normal rat kidneys and kidneys of animals subjected to 30 min of ischemia (renal artery ligation) followed by 12 hrs of reperfusion was performed. The results identified enhanced expression of Spermidine/Spermine N-1 acetyltransferase (SSAT), the rate limiting enzyme involved in the catabolism of polyamines, in IRI. Interestingly, thirty (30) min of ischemia (left anterior descending artery ligation) followed by 6-12 hrs of reperfusion resulted in the induction of SSAT in the injury zone in myocardium, with SSAT expression being almost undetectable in normal myocardium and increasing by >50-fold at 6 hrs of reperfusion. Enhanced SSAT expression in kidney and heart in IRI was associated with increased concentrations of putrescine, a mediator of apoptosis and a phenomenon indicative of increased activity of SSAT. Conditional overexpression of SSAT in cultured cells resulted in decreased cell growth. The studies outlined in this proposal will test the hypothesis that SSAT is a biomarker of cell injury and its increased expression reflects the extent of tissue damage associated with IRI in heart and kidney. We further hypothesize that enhanced expression of SSA T in kidney or heart leads to cell damage through depletion of polyamines, production of toxic metabolites (e.g. H202, putrescine and various aldehydes) and induction of apoptosis. To test these hypotheses, we propose to: 1. Examine the expression and regulation of SSAT and polyamine pathway in renal and heart IRI, 2. Ascertain the role of SSAT over expression on cell survival and susceptibility to injury in renal and cardiac IRI, and 3. Ascertain the mechanism of SSAT-mediated cell injury in renal and cardiac IRI. Insight into the expression and regulation of SSAT and other enzymes involved in polyamine metabolism in IRI will shed new lights into the pathophysiology of IRI in heart and kidney and may provide basis for novel diagnostic tests and therapeutic options targeted at early detection, prevention or treatment of ischemic heart attack and acute ischemic renal failure.
Funding Period: 2004-01-06 - 2005-12-31
more information: NIH RePORT

Top Publications

  1. ncbi Spermidine/spermine N1-acetyltransferase overexpression in kidney epithelial cells disrupts polyamine homeostasis, leads to DNA damage, and causes G2 arrest
    Kamyar Zahedi
    Division of Nephrology and Hypertension, Children s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
    Am J Physiol Cell Physiol 292:C1204-15. 2007
  2. ncbi Distinct and sequential upregulation of genes regulating cell growth and cell cycle progression during hepatic ischemia-reperfusion injury
    Sharon Barone
    Department of Medicine, University of Cincinnati, 231 Albert Sabin Way, MSB 259G, Cincinnati, Ohio 45267 0585, USA
    Am J Physiol Cell Physiol 289:C826-35. 2005
  3. pmc Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia
    Charuhas V Thakar
    Department of Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio 45267 0585, USA
    J Clin Invest 115:3451-9. 2005
  4. ncbi Stathmin-deficient mice develop fibrosis and show delayed recovery from ischemic-reperfusion injury
    Kamyar Zahedi
    Division of Nephrology and Hypertension, Children s Hospital Medical Center, Cincinnati, OH 45229 3039, USA
    Am J Physiol Renal Physiol 290:F1559-67. 2006
  5. pmc Spermidine/spermine-N1-acetyltransferase ablation protects against liver and kidney ischemia-reperfusion injury in mice
    Kamyar Zahedi
    Division of Nephrology and Hypertension, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabine Way, MSB 259G, Cincinnati, OH 45267 0585, USA
    Am J Physiol Gastrointest Liver Physiol 296:G899-909. 2009
  6. ncbi Ischemic and non-ischemic acute kidney injury cause hepatic damage
    Fereshteh Golab
    Department of Physiology, Tehran University of Medical Sciences, Iran
    Kidney Int 75:783-92. 2009

Scientific Experts

  • Kamyar Zahedi
  • Manoocher Soleimani
  • Alex B Lentsch
  • Sharon Barone
  • Fereshteh Golab
  • Charuhas V Thakar
  • Zhaohui Wang
  • Mehdi Hedayati
  • Hossein Arab
  • Maryam Zahmatkesh
  • Rebecca Schuster
  • Mehri Kadkhodaee
  • Tomohisa Okaya
  • Charles E Burnham
  • Robert A Casero
  • Hamid Rabb
  • Snezana Petrovic
  • Steve Rudich
  • Shannon Bevans
  • Kathy Tenrani
  • Monica P Revelo

Detail Information

Publications6

  1. ncbi Spermidine/spermine N1-acetyltransferase overexpression in kidney epithelial cells disrupts polyamine homeostasis, leads to DNA damage, and causes G2 arrest
    Kamyar Zahedi
    Division of Nephrology and Hypertension, Children s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
    Am J Physiol Cell Physiol 292:C1204-15. 2007
    ..We propose that in kidneys subjected to IRI, one mechanism through which increased expression of SSAT may cause cellular injury and organ damage is through induction of DNA damage and the disruption of cell cycle...
  2. ncbi Distinct and sequential upregulation of genes regulating cell growth and cell cycle progression during hepatic ischemia-reperfusion injury
    Sharon Barone
    Department of Medicine, University of Cincinnati, 231 Albert Sabin Way, MSB 259G, Cincinnati, Ohio 45267 0585, USA
    Am J Physiol Cell Physiol 289:C826-35. 2005
    ..The data further suggest that SSAT may play a role in the initiation of injury, whereas p21 and stathmin may be involved in the resolution and recovery after liver IRI...
  3. pmc Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia
    Charuhas V Thakar
    Department of Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio 45267 0585, USA
    J Clin Invest 115:3451-9. 2005
    ..We propose that TSP-1 is a novel regulator of ischemic damage in the kidney and may play an important role in the pathophysiology of ischemic kidney failure...
  4. ncbi Stathmin-deficient mice develop fibrosis and show delayed recovery from ischemic-reperfusion injury
    Kamyar Zahedi
    Division of Nephrology and Hypertension, Children s Hospital Medical Center, Cincinnati, OH 45229 3039, USA
    Am J Physiol Renal Physiol 290:F1559-67. 2006
    ....
  5. pmc Spermidine/spermine-N1-acetyltransferase ablation protects against liver and kidney ischemia-reperfusion injury in mice
    Kamyar Zahedi
    Division of Nephrology and Hypertension, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabine Way, MSB 259G, Cincinnati, OH 45267 0585, USA
    Am J Physiol Gastrointest Liver Physiol 296:G899-909. 2009
    ..These studies indicate that SSAT-deficient animals are protected against IRI and suggest that SSAT is an important mediator of the tissue damage in IRI...
  6. ncbi Ischemic and non-ischemic acute kidney injury cause hepatic damage
    Fereshteh Golab
    Department of Physiology, Tehran University of Medical Sciences, Iran
    Kidney Int 75:783-92. 2009
    ..Our study shows that acute kidney ischemia or renal failure activates oxidative stress and promotes inflammation, apoptosis, and tissue damage in hepatocytes...