Zhao, W., Iskandar, S., Kooshki, M., Sharpe, J. G., Payne, V. and Robbins, M. E. Knocking Out Peroxisome Proliferator-Activated Receptor (PPAR) α Inhibits Radiation-Induced Apoptosis in the Mouse Kidney through Activation of NF-κB and Increased Expression of IAPs. Radiat. Res. 167, 581–591 (2007).
Peroxisome proliferator-activated receptor (PPAR) α, 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 PPARα knockout mice would exhibit decreased radiation-induced apoptosis due to exacerbated activation of NF-κB (NFKB) and expression of pro-survival factors. Thirty wild-type mice (29S1/SvImJ) and 30 PPARα knockout mice were irradiated with a single total-body dose 10 Gy of 137Cs γ 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 PPARα 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-κB DNA-binding activity, IκBα phosphorylation, and expression of other antiapoptosis factors in the PPARα knockout mouse kidneys but not in wild-type animals. These data support the hypothesis that the loss of PPARα expression leads to the suppression of radiation-induced apoptosis in the mouse kidney, mediated through activation of NF-κB and up-regulation of anti-apoptosis factors.