Cell Biology – Immunology – Pathology

Kidney International (2004) 65, 499–509; doi:10.1111/j.1523-1755.2004.00415.x

5-Aminoisoquinolinone reduces renal injury and dysfunction caused by experimental ischemia/reperfusion

PRABAL K CHATTERJEE1, BRISTI E CHATTERJEE, HELENE PEDERSEN, AHILA SIVARAJAH, MICHELLE C MCDONALD, HELDER MOTA-FILIPE, PAUL A J BROWN, KEITH N STEWART, SALVATORE CUZZOCREA, MICHAEL D THREADGILL and CHRISTOPH THIEMERMANN

Department of Experimental Medicine, Nephrology & Critical Care, The William Harvey Research Institute, Queen Mary—University of London, United Kingdom; Laboratory of Pharmacology, Faculty of Pharmacy, University of Lisbon, Portugal; Department of Pathology, University of Aberdeen, United Kingdom; Department of Medicine & Therapeutics, University of Aberdeen, United Kingdom; Department of Clinical and Experimental Medicine & Pharmacology, University of Messina, Italy; and Department of Pharmacy & Pharmacology, University of Bath, United Kingdom

Correspondence: Professor Christoph Thiemerman, School of Pharmacy & Biomolecular Sciences, University of Brighton, Cockcroft Building, Moulsecoomb, Brighton, BN2 4GJ, United Kingdom

1Current address: Department of Pharmacology, School of Pharmacy & Biomolecular Sciences, University of Brighton, Cockcroft Building, Moulsecoomb, Brighton, BN2 4GJ, United Kingdom

Received 26 March 2003; Revised 21 May 2003; Re-revised 9 September 2003; Accepted 22 September 2003.

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Abstract

5-Aminoisoquinolinone reduces renal injury and dysfunction caused by experimental ischemia/reperfusion.

Background

 

Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the development of ischemia/reperfusion (I/R) injury. The aim of this study was to investigate the effects of a water-soluble and potent PARP inhibitor, 5-aminoisoquinolinone (5-AIQ), on the renal injury and dysfunction caused by oxidative stress of the rat kidney in vitro and in vivo.

Methods

 

Primary cultures of rat renal proximal tubular cells, subjected to oxidative stress caused by hydrogen peroxide (H2O2), were incubated with increasing concentrations of 5-AIQ (0.01 to 1 mmol/L) after which PARP activation, cellular injury, and cell death were measured. In in vivo experiments, anesthetized male Wistar rats were subjected to renal bilateral ischemia (45 minutes) followed by reperfusion (6 hours) in the absence or presence of 5-AIQ (0.3 mg/kg) after which renal dysfunction, injury and PARP activation were assessed.

Results

 

Incubation of proximal tubular cells with H2O2 caused a substantial increase in PARP activity, cellular injury, and cell death, which were all significantly reduced in a concentration-dependent by 5-AIQ [inhibitory concentration 50 (IC50) approx 0.03 mmol/L]. In vivo, renal I/R resulted in renal dysfunction, injury, and PARP activation, primarily in the proximal tubules of the kidney. Administration of 5-AIQ significantly reduced the biochemical and histologic signs of renal dysfunction and injury and markedly reduced PARP activation caused by I/R.

Conclusion

 

This study demonstrates that 5-AIQ is a potent, water soluble inhibitor of PARP activity, which can significantly reduce (1) cellular injury and death caused to primary cultures of rat proximal tubular cells by oxidative stress in vitro, and (2) renal injury and dysfunction caused by I/R of the kidney of the rat in vivo.

Keywords:

5-aminoisoquinolinone, ischemia, oxidative stress, poly (ADP-ribose) polymerase, rat, reperfusion-injury

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