Prevention of apoptotic and necrotic cell death, caspase-3 activation, and renal dysfunction by melatonin after ischemia/reperfusion.
The pineal hormone melatonin has been reported to protect tissue from oxidative damage. This study was designed to determine whether melatonin could prevent cell events leading to tissue injury and renal dysfunction after ischemia/reperfusion (I/R). Using an in vivo rat model of I/R, we show a significant increase in kidney malondialdehyde concentrations, reflecting lipid peroxidation, and cell apoptosis measured by TUNEL staining. This apoptotic cell death was associated with an increase in the activity of the proapoptotic factor caspase-3, determined by fluorometric protease activity assay. Histomorphological analysis of ischemic kidneys revealed that the most extensive tubular necrosis occurred at 24 and 48 h after reperfusion, which correlated with peak elevations in blood urea nitrogen and creatinine. Rat pretreatment with melatonin prevented lipid peroxidation, cell apoptosis, and necrosis and blocked caspase-3 activity. The prevention of tissue injury was associated with the improvement of renal function as shown by the decrease in blood urea nitrogen and creatinine concentrations. The demonstration that melatonin prevents postreperfusion apoptotic and necrotic cell death and improves renal function suggests that melatonin may represent a novel therapeutic approach for prevention of I/R injury.
Kunduzova
Oxana R
OR
INSERM U388, Institut Louis Bugnard, CHU Rangueil, Bat. L3, 31403 Toulouse Cedex 4, France.
Escourrou
Ghislaine
G
Seguelas
Marie-Helene
MH
Delagrange
Philippe
P
De La Farge
France
F
Cambon
Claudie
C
Parini
Angelo
A
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001806:Blood Urea Nitrogen; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D003404:Creatinine / Q000097:blood; D004789:Enzyme Activation / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D007684:Kidney Tubules / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008550:Melatonin / Q000494:pharmacology*; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D015427:Reperfusion Injury / Q000503:physiopathology*
D000975:Antioxidants; D003404:Creatinine; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D008550:Melatonin