Knocking out peroxisome proliferator-activated receptor (PPAR) alpha inhibits radiation-induced apoptosis in the mouse kidney through activation of NF-kappaB and increased expression of IAPs.
Peroxisome proliferator-activated receptor (PPAR) alpha, a member of the ligand-activated nuclear receptor superfamily, plays an important role in lipid metabolism and glucose homeostasis and is highly expressed in the kidney. The present studies were aimed at testing the hypothesis that PPARalpha knockout mice would exhibit decreased radiation-induced apoptosis due to exacerbated activation of NF-kappaB (NFKB) and expression of pro-survival factors. Thirty wild-type mice (29S1/SvImJ) and 30 PPARalpha knockout mice were irradiated with a single total-body dose 10 Gy of (137)Cs gamma rays; controls were sham-irradiated. Tissue samples were collected at 3, 6, 12, 24 and 48 h postirradiation. Apoptosis was quantified using immunohistochemical staining for apoptotic bodies and cleaved caspase 3. Radiation-induced apoptosis was observed in both mouse strains in a time-dependent manner. However, the level of apoptosis was significantly suppressed in PPARalpha knockout mice compared with wild-type mice at 6 h postirradiation (P < 0.05). This inhibition of radiation-induced apoptosis was associated with time-dependent increases in NF-kappaB DNA-binding activity, IkappaBalpha phosphorylation, and expression of other antiapoptosis factors in the PPARalpha knockout mouse kidneys but not in wild-type animals. These data support the hypothesis that the loss of PPARalpha expression leads to the suppression of radiation-induced apoptosis in the mouse kidney, mediated through activation of NF-kappaB and up-regulation of anti-apoptosis factors.
Zhao
Weiling
W
Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. wzhao@wfubmc.edu
Iskandar
Samy
S
Kooshki
Mitra
M
Sharpe
Jessica G
JG
Payne
Valerie
V
Robbins
Mike E
ME
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D020672:I-kappa B Proteins / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000528:radiation effects*; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics; D048068:PPAR-beta / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
D020672:I-kappa B Proteins; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D047493:PPAR alpha; D047495:PPAR gamma; D048068:PPAR-beta; D019253:Proto-Oncogene Proteins c-bcl-2; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA