Potential role of poly(ADP-ribose) polymerase (PARP) activation in methotrexate-induced nephrotoxicity and tubular apoptosis.
Nephrotoxicity is one of the serious dose-limiting complications of methotrexate (MTX) when used in the treatment of various malignancies and nononcological diseases. The aim of this study was to investigate the role of poly(adenosine diphosphate ribose) polymerase (PARP) activity in MTX-induced nephrotoxicity. Rats were divided into 4 groups as control, MTX treated (MTX, 7 mg/kg per d, intraperitoneally [ip], once daily for 3 consecutive days), MTX plus 1,5-isoquinelinediol (ISO, a PARP inhibitor, 3 mg/kg per d, i.p.) treated, or ISO treated. Histopathology of kidneys was evaluated by light microscopy. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay was used to analyze apoptosis in kidney sections. Blood urea nitrogen (BUN), serum creatinine, and urinary N-acetyl-β-d-glucosaminidase (NAG) were used as biochemical markers of MTX-induced renal injury. Our results showed that MTX administration significantly increased BUN, serum creatinine, and urinary NAG levels. The PARP-1 and PAR (a product of PARP activity) expression and apoptotic cell death were also markedly increased in renal tubules after MTX administration. The ISO treatment attenuated MTX-induced renal injury, as indicated by BUN and serum creatinine levels, urinary NAG excretion, and renal histology. The PARP inhibitor treatment reduced PARP-1 and PAR expression to levels similar to that of controls. These results revealed that ISO may have a protective effect against the nephrotoxic effects of MTX by inhibiting PARP activation. This is the first study that demonstrates the role of PARP activation in MTX-induced nephrotoxicity and tubular apoptosis.
Department of Pharmacology, Akdeniz University, Antalya 07070, Turkey. stasatargil@akdeniz.edu.tr
Selvinaz
S
Dalaklioglu
Pinar
P
Sahin
Ece Gungor
EG
Ordueri
Ciler
C
Celik-Ozenci
Arda
A
Tasatargil
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects; D018501:Antirheumatic Agents / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D005493:Folic Acid Antagonists / Q000009:adverse effects; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007546:Isoquinolines; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000009:adverse effects*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D020011:Protective Agents / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D000964:Antimetabolites, Antineoplastic; D018501:Antirheumatic Agents; D005493:Folic Acid Antagonists; D007166:Immunosuppressive Agents; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020011:Protective Agents; D011804:Quinolines; C095653:1,5-dihydroxyisoquinoline; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D008727:Methotrexate