BACKGROUND: These experiments sought to evaluate the effects of PJ34, a poly-ADP-ribose polymerase inhibitor, on molecular indices of renal injury, mitochondrial function, tissue thrombosis, and fibrinolysis after thoracic aortic ischemia/reperfusion (TAR). METHODS: Forty-three 129S1/SvImj mice were subjected to 11 minutes of TAR followed by 48 hours of reperfusion. Experimental groups included untreated normal saline (NS) controls (UC), (n=15, 0.5 mL NS i.p.) or PJ34 (PJ) (n=17, PJ34 10 mg/kg ip, 1 hour before and after TAR). Sham (SH) mice (n=11) underwent median sternotomy (heparin, NS i.p.) without TAR. Forty-eight hours after TAR or sham operation, kidney mitochondrial activity (using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium [MTT]), D-dimer, and thrombin-antithrombin III (TAT) complex levels were measured. Levels of messenger RNA for neutrophil gelatinase-associated lipocalin (NGAL), a marker for renal injury, were also measured by reverse transcriptase-polymerase chain reaction. RESULTS: PJ34 improves renal mitochondrial activity after 48 hours of TAR, compared with untreated control animals (UC, 87.6 +/- 2.2%; PJ, 151.4 +/- 9.5%; P < .001). PJ34 did not alter the increase in renal D-dimer levels by 48 hours reperfusion (UC, 1.37 +/- 0.09 U; PJ, 1.1 +/- 0.14 U; SH, 0.82 +/- 0.06 U; P < .05). TAR did not alter renal levels of TAT expression among groups (UC, 0.103 +/- 0.034; PJ, 0.067 +/- 0.008; SH, 0.106 +/- 0.027; P=.619). The incidence of significantly increased NGAL among UC mice was 1415 +/- 823.6 (n=12), compared with 29.6 +/- 20.8 (n=10) in the PJ34-treated group (P < .014). CONCLUSIONS: PJ34 preserves renal mitochondrial activity and decreases steady-state levels of NGAL after TAR. TAR did increase markers of fibrinolysis in renal tissue but their increase did not correlate with renal injury or PJ34 treatment. These studies indicate that PJ34 confers protection against TAR and suggest that PARP may represent a novel target for reducing perioperative renal injury.
BACKGROUND: These experiments sought to evaluate the effects of PJ34, a poly-ADP-ribose polymerase inhibitor, on molecular indices of renal injury, mitochondrial function, tissue thrombosis, and fibrinolysis after thoracic aortic ischemia/reperfusion (TAR). METHODS: Forty-three 129S1/SvImj mice were subjected to 11 minutes of TAR followed by 48 hours of reperfusion. Experimental groups included untreated normal saline (NS) controls (UC), (n=15, 0.5 mL NS i.p.) or PJ34 (PJ) (n=17, PJ34 10 mg/kg ip, 1 hour before and after TAR). Sham (SH) mice (n=11) underwent median sternotomy (heparin, NS i.p.) without TAR. Forty-eight hours after TAR or sham operation, kidney mitochondrial activity (using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium [MTT]), D-dimer, and thrombin-antithrombin III (TAT) complex levels were measured. Levels of messenger RNA for neutrophil gelatinase-associated lipocalin (NGAL), a marker for renal injury, were also measured by reverse transcriptase-polymerase chain reaction. RESULTS: PJ34 improves renal mitochondrial activity after 48 hours of TAR, compared with untreated control animals (UC, 87.6 +/- 2.2%; PJ, 151.4 +/- 9.5%; P < .001). PJ34 did not alter the increase in renal D-dimer levels by 48 hours reperfusion (UC, 1.37 +/- 0.09 U; PJ, 1.1 +/- 0.14 U; SH, 0.82 +/- 0.06 U; P < .05). TAR did not alter renal levels of TAT expression among groups (UC, 0.103 +/- 0.034; PJ, 0.067 +/- 0.008; SH, 0.106 +/- 0.027; P=.619). The incidence of significantly increased NGAL among UC mice was 1415 +/- 823.6 (n=12), compared with 29.6 +/- 20.8 (n=10) in the PJ34-treated group (P < .014). CONCLUSIONS: PJ34 preserves renal mitochondrial activity and decreases steady-state levels of NGAL after TAR. TAR did increase markers of fibrinolysis in renal tissue but their increase did not correlate with renal injury or PJ34 treatment. These studies indicate that PJ34 confers protection against TAR and suggest that PARP may represent a novel target for reducing perioperative renal injury.
Authors: Rosanna Vaschetto; Jan W Kuiper; René J P Musters; Etto C Eringa; Francesco Della Corte; Kanneganti Murthy; A B Johan Groeneveld; Frans B Plötz Journal: Crit Care Date: 2010-03-26 Impact factor: 9.097
Authors: Thomas L Nickolas; Matthew J O'Rourke; Jun Yang; Meghan E Sise; Pietro A Canetta; Nicholas Barasch; Charles Buchen; Faris Khan; Kiyoshi Mori; James Giglio; Prasad Devarajan; Jonathan Barasch Journal: Ann Intern Med Date: 2008-06-03 Impact factor: 25.391