Inhibition of poly(ADP-ribose) polymerase attenuates ischemic renal injury in rats.
The enzyme, poly(ADP-ribose) polymerase (PARP), effects repair of DNA after ischemia-reperfusion (I/R) injury to cells in nerve and muscle tissue. However, its activation in severely damaged cells can lead to ATP depletion and death. We show that PARP expression is enhanced in damaged renal proximal tubules beginning at 6-12 h after I/R injury. Intraperitoneal administration of PARP inhibitors, benzamide or 3-amino benzamide, after I/R injury accelerates the recovery of normal renal function, as assessed by monitoring the levels of plasma creatinine and blood urea nitrogen during 6 days postischemia. PARP inhibition leads to increased cell proliferation at 1 day postinjury as assessed by proliferating cell nuclear antigen and improves the histopathological appearance of kidneys examined at 7 days postinjury. Furthermore, inhibition of PARP increases levels of ATP measured at 24 h postischemia compared with those in vehicle-treated animals. Our data indicate that PARP activation is a part of the cascade of molecular events that occurs after I/R injury in the kidney. Although caution is advised, transient inhibition of PARP postischemia may constitute a novel therapy for acute renal failure.
Martin
D R
DR
George M. O'Brien Center, Renal Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Lewington
A J
AJ
Hammerman
M R
MR
Padanilam
B J
BJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D004260:DNA Repair; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D007668:Kidney / Q000098:blood supply* / Q000737:chemistry; D008297:Male; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*
D001549:Benzamides; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; C037689:benzamide; C025160:3-aminobenzamide; D000255:Adenosine Triphosphate