[HTML][HTML] Peroxisome proliferator-activated receptor-α is renoprotective in doxorubicin-induced glomerular injury

Y Zhou, X Kong, P Zhao, H Yang, L Chen, J Miao… - Kidney international, 2011 - Elsevier
Y Zhou, X Kong, P Zhao, H Yang, L Chen, J Miao, X Zhang, J Yang, J Ding, Y Guan
Kidney international, 2011Elsevier
Doxorubicin (DOX) is an anthracycline antibiotic utilized in antitumor therapy; however, its
clinical use is frequently impeded by renal toxic effects. As peroxisome proliferator-activated
receptor-α (PPAR-α) has renoprotective effects in drug-related kidney injuries, we tested its
ability to inhibit DOX-induced renal injury. Although both male PPAR-α knockout mice and
their wild-type littermates (pure 129/SvJ background) had significant proteinuria 4 weeks
after DOX treatment, those with deletion of PPAR-α had more severe proteinuria. This was …
Doxorubicin (DOX) is an anthracycline antibiotic utilized in antitumor therapy; however, its clinical use is frequently impeded by renal toxic effects. As peroxisome proliferator-activated receptor-α (PPAR-α) has renoprotective effects in drug-related kidney injuries, we tested its ability to inhibit DOX-induced renal injury. Although both male PPAR-α knockout mice and their wild-type littermates (pure 129/SvJ background) had significant proteinuria 4 weeks after DOX treatment, those with deletion of PPAR-α had more severe proteinuria. This was associated with more serious podocyte foot process effacement compared with wild-type mice. In contrast, the PPAR-α agonist fenofibrate effectively reduced proteinuria and attenuated DOX-induced podocyte foot process effacement. Consistently, glomerular nephrin expression was significantly lower in the knockout compared with wild-type mice following DOX treatment. Fenofibrate therapy significantly blunted the reduction in glomerular nephrin levels in DOX-treated wild-type mice. In cultured podocytes, DOX induced apoptosis, increased cleaved caspase-3 levels, and decreased Bcl-2 expression, all attenuated by pretreatment with fenofibrate. Thus, PPAR-α deficiency exacerbates DOX-related renal injury, in part, due to increased podocyte apoptosis.
Elsevier