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02 May 2003

Inhibitors of poly(ADP-ribose) polymerase activity as interventions against renal ischemia/reperfusion injury and acute renal failure

P. Chatterjee, M. McDonald, M. Threadgill, C. Thiemermann

Med Sci Monit 2003; 9(1): 10-0 :: ID: 15056

Abstract

Excessive activation of PARP contributes to the renal dysfunction and injury caused by reactive oxygen species (ROS), nitric oxide and peroxynitrite [1]. However, most inhibitors of PARP activity are either weak inhibitors (e.g. 3-aminobenzamide) or are soluble in dimethyl sulphoxide (e.g. 5-dihydroxyisoquinoline). We therefore investigated the effects of the water-soluble PARP inhibitor, 5-aminoisoquinolinone (5-AIQ), on the (i) renal dysfunction caused by 45 min ischaemia followed by 6 h reperfusion (I/R) in vivo and (ii) cytotoxicity caused by exposure of rat proximal tubular (PT) cells to oxidative stress (1 mM H2O2 for 4 h) in vitro.Renal I/R produced a significant increase in serum creatinine levels (indicating renal dysfunction) which was reduced significantly by 5-AIQ (Table 1). Incubation of rat PT cells with H2O2 increased LDH significantly (indicating renal cytotoxicity) (Table 2), however, incubation with H2O2 and 5-AIQ produced a significant reduction in LDH release (Table 2).Thus we propose that PARP inhibitors may be useful in conditions which involve renal ischaemia and reperfusion (e.g. renal transplantation).References: 1.Chatterjee PK, Thiemermann C: Poly(ADP-ribose) polymerase inhibitors and acute renal failure. In: Zhang J (ed.): Therapeutic Utilities of PARP Inhibitors. CRC Press; Boca Raton, 2002, pp. 149-168

Keywords: renal, Kidney, proximal tubular cells, poly(ADP-ribose) polymerase, poly(ADP-ribose) polymerase inhibitor, 5-aminoisoquinolinone, 5-dihydroxyisoquinolinoline

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750