Poly(ADP-ribose) polymerase (PARP) activation after free-radical-induced DNA damage depletes cellular energy stores and participates in ischemia-reflow injury. We studied the potential protective effect of the water-soluble PARP inhibitor 3-aminobenzamide (3-AB) in a rat model of acute renal failure (ARF) from combined administration of radiocontrast, indomethacin and Nω-nitro-L-arginine methyl ester. Kidney function at 24 h was better preserved in rats treated with 3-AB as compared to control animals. However, the extent of tubular hypoxic damage was not significantly mitigated. It is concluded that PARP inhibition may attenuate renal dysfunction in this model of ARF with medullary hypoxic tubular injury even while the extent of tubular necrosis is not significantly altered. Further studies of this dyssynchrony of structure and function may provide important insights into the sequence of events that promotes renal failure after medullary injury.

1.
Beeri R, Symon Z, Brezis M, Ben-Sasson SA, Baehr PH, Rosen S, Zager RA: Rapid DNA fragmentation from hypoxia along the thick ascending limb of rat kidneys. Kidney Int 1995;47:1806–1810.
2.
Ame JC, Rolli V, Schreiber V, Niedergang C, Apiou F, Decker P, Muller S, Hoger T, Menissier-de-Murcia J, de Murcia G: PARP-2, a novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. J Biol Chem 1999;274:17860–17868.
3.
Alvarez-Gonzalez R, Watkins TA, Gill PK, Reed JL, Mendoza-Alvarez H: Regulatory mechanisms of poly(ADP-ribose) polymerase. Moll Cell Biochem 1999;193:19–22.
4.
Love S: Oxidative stress in brain ischemia. Brain Pathol 1999;9:119–131.
5.
Szabo C, Dawson VL: Role of poly(ADP-ribose) synthetase in inflammation and ischemia-reperfusion. Trends Pharmacol Sci 1998;19:287–298.
6.
Abdelkarim GE, Gertz K, Harms C, Katchanov J, Dirnagl U, Szabo C, Endres M: Protective effects of PJ34, a novel, potent inhibitor of poly(ADP- ribose) polymerase (PARP) in in vitro and in vivo models of stroke. Int J Mol Med 2001;7:255–260.
7.
McDonald MC, Filipe HM, Thiemermann C: Effects of inhibitors of the activity of poly(ADP-ribose) synthetase on the organ injury and dysfunction caused by haemorrhagic shock. Br J Pharmacol 1999;128:1339–1345.
8.
Jagtap P, Soriano FG, Virag L, Liaudet L, Mabley J, Szabo E, Hasko G, Marton A, Lorigados CB, Gallyas F, Sumegi B, Hoyt DG, Baloglu E, VanDuzer J, Salzman AL, Southan GJ, Szabo C: Novel phenanthridinone inhibitors of poly(adenosine 5′-diphosphate-ribose) synthetase: Potent cytoprotective and antishock agents. Crit Care Med 2002;30:1071–1082.
9.
Thiemermann C, Bowes J, Myint FP, Vane JR: Inhibition of the activity of poly(ADP ribose) synthetase reduces ischemia-reperfusion injury in the heart and skeletal muscle. Proc Natl Acad Sci USA 1997;94:679–683.
10.
Faro R, Toyoda Y, McCully JD, Jagtap P, Szabo E, Virag L, Bianchi C, Levitsky S, Szabo C, Sellke FW: Myocardial protection by PJ34, a novel potent poly(ADP-ribose) synthetase inhibitor. Ann Thorac Surg 2002;73:575–581.
11.
Pacher P, Liaudet L, Bai P, Virag L, Mabley JG, Hasko G, Szabo C: Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure. J Pharmacol Exp Ther 2002;300:862–867.
12.
Racz I, Tory K, Gallyas F, Berente Z, Osz E, Jaszlits L, Bernath S, Sumegi B, Rabloczky G, Literati-Nagy P: BGP-15 – a novel poly(ADP-ribose) polymerase inhibitor – protects against nephrotoxicity of cisplatin without compromising its antitumor activity. Biochem Pharmacol 2002;63:1099–1111.
13.
Liaudet L, Pacher P, Mabley JG, Virag L, Soriano FG, Hasko G, Szabo C: Activation of poly(ADP-ribose) polymerase-1 is a central mechanism of lipopolysaccharide-induced acute lung inflammation. Am J Respir Crit Care Med 2002;165:372–377.
14.
Goldfarb RD, Marton A, Szabo E, Virag L, Salzman AL, Glock D, Akhter I, McCarthy R, Parrillo JE, Szabo C: Protective effect of a novel, potent inhibitor of poly(adenosine 5′-diphosphate-ribose) synthetase in a porcine model of severe bacterial sepsis. Crit Care Med 2002;30:974–980.
15.
Pacher P, Mabley JG, Soriano FG, Liaudet L, Komjati K, Szabo C: Endothelial dysfunction in aging animals: The role of poly(ADP-ribose) polymerase activation. Br J Pharmacol 2002;135:1347–1350.
16.
Soriano FG, Pacher P, Mabley J, Liaudet L, Szabo C: Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase. Circ Res 2001;89:684–691.
17.
Pacher P, Liaudet L, Soriano FG, Mabley JG, Szabo E, Szabo C: The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes. Diabetes 2002;51:514–521.
18.
Garcia Soriano F, Virag L, Jagtap P, Szabo E, Mabley JG, Liaudet L, Marton A, Hoyt DG, Murthy KG, Salzman AL, Southan GJ, Szabo C: Diabetic endothelial dysfunction: The role of poly(ADP-ribose) polymerase activation. Nat Med 2001;7:108–113.
19.
Szabo G, Bahrle S, Stumpf N, Sonnenberg K, Szabo EE, Pacher P, Csont T, Schulz R, Dengler TJ, Liaudet L, Jagtap PG, Southan GJ, Vahl CF, Hagl S, Szabo C: Poly(ADP-ribose) polymerase inhibition reduces reperfusion injury after heart transplantation. Circ Res 2002;90:100–106.
20.
Filipovic DM, Meng X, Reeves WB: Inhibition of PARP prevents oxidant-induced necrosis but not apoptosis in LLC-PK1 cells. Am J Physiol 1999;277:F428–F436.
21.
Lipton P: Ischemic cell death in brain neurons. Physiol Rev 1999;79:1431–1568.
22.
Feldenberg LR, Thevananther S, del Rio M, de Leon M, Devarajan P: Partial ATP depletion induces Fas- and caspase-mediated apoptosis in MDCK cells. Am J Physiol 1999;276:F837–F846.
23.
Chien CT, Lee PH, Chen CF, Ma MC, Lai MK, Hsu SM: De novo demonstration and co-localization of free-radical production and apoptosis formation in rat kidney subjected to ischemia/reperfusion. J Am Soc Nephrol 2001;12:973–982.
24.
Aoufouchi S, Yelamos J, Milstein C: Inhibition of apoptosis of PARP (–)/(–) cell line transfected with PARP DNA-binding domain mutants. J Mol Biol 1999;290:943–949.
25.
Boulares AH, Yakovlev AG, Ivanova V, Stoica BA, Wang G, Iyer S, Smulson M: Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis. Capsase 3-resistant PARP mutant increases rates of apoptosis in transfected cells. J Biol Chem 1999;274:22932–22949.
26.
Richardson DS, Allen PD, Kelsey SM, Newland AC: Effects of PARP inhibition on drug and FAS-induced apoptosis in leukemic cells. Adv Exp Med Biol 1999;457:267–279.
27.
Roberts MJ, Curtin NJ, Durkacz BW, Golding BT, Griffin RJ, Halls AG, Newell DR, Srinivasan S: Induction of apoptosis in a panel of human cell lines using NU1025, a novel potent inhibitor of poly(ADP) ribose polymerase. Proc Annu Meet Am Soc Cancer Res 1997;38:A1301.
28.
Bowman KJ, Calvert AH, Curtin NJ, Golding BT, Griffin RJ, Newell DR, Srinivasan S, White A: Potentiation of the cytotoxicity of anti-cancer agents by novel poly(ADP-ribose) polymerase inhibitors. Proc Annu Meet Am Soc Cancer Res 1996;37:A2564.
29.
Chatterjee PK, Zacharowski K, Cuzzocrea S, Otto M, Thiemermann C: Inhibitors of poly(ADP-ribose) synthetase reduce renal ischemia-reperfusion injury in the anesthetized rat in vivo. FASEB J 2000;14:641–651.
30.
Martin DR, Lewington AJ, Hammerman MR, Padanilam BJ: Inhibition of poly(ADP-ribose) polymerase attenuates ischemic renal injury in rats. Am J Physiol 2000;279:R1834–R1840.
31.
Soriano FG, Liaudet L, Szabo E, Virag L, Mabley JG, Pacher P, Szabo C: Resistance to acute septic peritonitis in poly(ADP-ribose) polymerase-1-deficient mice. Shock 2002;17:286–292.
32.
Agmon Y, Peleg H, Greenfeld Z, Rosen S, Brezis M: Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat. J Clin Invest 1994;94:1069–1075.
33.
Heyman SN, Fuchs S, Yafe R, Beeri R, Elazarian L, Brezis M, Rosen S: Renal microcirculation and tissue damage during acute ureteral obstruction: The effect of saline infusion, indomethacin and radiocontrast. Kidney Int 1997;51:653–663.
34.
Lieberthal W, Nigam SK: Acute renal failure. I. Relative importance of proximal vs. distal tubular injury. Am J Physiol 1998;275:F623–F632.
35.
Heyman SN, Lieberthal W, Rogiers P, Bonventre JV: Animal models of acute tubular necrosis. Curr Opin Crit Care 2002;8:526–534.
36.
Shanley PF, Rosen MD, Brezis M, Silva P, Epstein FH, Rosen H: Topography of focal proximal tubular necrosis after ischemia with reflow in the rat kidney. Am J Pathol 1986;122:462–468.
37.
Heyman SN, Rosen S, Brezis M: The renal medulla: Life at the edge of anoxia. Blood Purif 1997;15:232–242.
38.
Heyman SN, Shina A, Brezis M, Rosen S: Proximal tubular injury attenuates outer medullary hypoxic damage. Studies in the isolated perfused kidney. Exp Nephrol 2002;10:259–266.
39.
Kurnik BR, Allgren RL, Genter FC, Solomon RJ, Bates ER, Weisberg LS: Prospective study of atrial natriuretic peptide for the prevention of radiocontrast-induced nephropathy. Am J Kidney Dis 1998;31:674–680.
40.
Heyman SN, Brezis M, Epstein FH, Spokes K, Rosen S: Effect of glycine and hypertrophy on renal outer medullary hypoxic injury in ischemia reflow and contrast nephropathy. Am J Kidney Dis 1992;19:578–586.
41.
Heyman SN, Brezis M, Greenfeld Z, Rosen S: Protective role of furosemide and saline in radiocontrast-induced acute renal failure in the rat. Am J Kidney Dis 1989;14:377–385.
42.
Rosenberger C, Heyman SN, Rosen S, Frei U, Bachmann S, Eckardt KU: Expression of hypoxia-inducible factors 1α and 2α in acute renal failure. J Am Soc Nephrol 2002;13:136A–137A.
43.
Brezis M, Kopolovic J, Rosen S: Hypoxic injury to medullary thick ascending limbs in perfused rat kidneys: Reversible and irreversible phases. J Electron Microsc Tech 1988;9:293–298.
44.
Heyman SN, Brezis M, Epstein FH, Spokes K, Silva P, Rosen S: Early renal medullary hypoxic injury from radiocontrast and indomethacin. Kidney Int 1991;40:632–642.
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