Protective effects of peroxisome proliferator-activated receptor gamma ligand on apoptosis and hepatocyte growth factor induction in renal ischemia-reperfusion injury.
BACKGROUND
Renal ischemia-reperfusion injury affects the long-term outcome of renal graft survival. Thiazolidinediones (TZDs), synthetic peroxisome proliferator-activated receptor (PPAR)-gamma ligands, have been shown to exert therapeutic effects upon renal ischemia-reperfusion injury far beyond their use as insulin sensitizers. It has also been reported that hepatocyte growth factor (HGF) has a beneficial effect on renal ischemia-reperfusion injury and that TZDs induce increased HGF mRNA expression and protein secretion. We investigated the effect of troglitazone, one of the TZDs, in a rat model of renal ischemia-reperfusion injury.


METHODS
A 45-minute period of warm renal ischemia was induced by bilateral clamping at 37 degrees C with rats being sacrificed before the onset of ischemia and at 2, 4, 6, and 12 hr after reperfusion. The expression of PPAR-gamma was measured by reverse-transcriptase polymerase chain reaction (RT-PCR) and western blotting while the production of HGF was investigated by RT-PCR and immunohistochemistry. The effect of troglitazone treatment on the level of apoptosis was determined by staining for cleaved caspase-3 and single-stranded DNA (ssDNA).


RESULTS
The numbers of cleaved caspase-3 and ssDNA positive cells were decreased in rats treated with troglitazone. The production of HGF mRNA and protein was most intense at 4 hr. The expression of PPAR-gamma and HGF was increased in the group treated with troglitazone compared with the control group. CONCLUSIONS.: Pretreatment of rats with the PPAR-gamma ligand troglitazone decreased apoptotic cell death in renal ischemia-reperfusion injury as a result of the induction of HGF.
Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Shigehiro
S
Doi
Takao
T
Masaki
Tetsuji
T
Arakawa
Shunsuke
S
Takahashi
Toru
T
Kawai
Ayumu
A
Nakashima
Takayuki
T
Naito
Nobuoki
N
Kohno
Noriaki
N
Yorioka
D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002839:Chromans / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects*; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism; D008024:Ligands; D008297:Male; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D000077288:Troglitazone; D014508:Urea / Q000097:blood; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use
D002839:Chromans; D008024:Ligands; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D017228:Hepatocyte Growth Factor; D014508:Urea; D003404:Creatinine; D053148:Caspase 3; D000077288:Troglitazone