Insight into the Mechanism of Doxorubicin-induced Nephrotoxicity through Gene Expression Analysis of Oxidative Stress, Kidney Injury and Inflammation Markers
Insight into the Mechanism of Doxorubicin-induced Nephrotoxicity through Gene Expression Analysis of Oxidative Stress, Kidney Injury and Inflammation Markers
Uzma Jabeen1, Asmat Salim2*, Irfan Khan2, Nadia Naeem3 and Rubina Mushtaq4
ABSTRACT
Doxorubicin (DOX), a valuable anti-cancer drug can cause multi-organ toxicities. Among several suggested mechanisms, the role of oxidative stress remains obscure, though it is the most probable mechanism for its cardiotoxic effect. The main focus of this study is to analyze the mechanism of renal toxicity caused by this chemotherapeutic drug. As reactive oxygen species are significant regulators of transcription factors and gene expression, this study was aimed at analyzing the expression levels of genes that are induced in response to oxidative stress following DOX administration to rats. DOX was administered to rats intraperitoneally at 3 mg/kg at alternate days for two weeks. Kidney tissues were harvested and the mRNA levels of glutathione peroxidase-1(Gpx1), NAD(P)H quinone dehydrogenase 1 (Nqo1), 24-dehydrocholesterol reductase (Dhcr24), dual oxidase 2 (Duox2), and isocitrate dehydrogenase-1 (Idh1) were analyzed in the kidney tissues by RT-PCR. Extent of injury was analyzed by the change in expression of kidney injury biomarkers, kidney injury molecule-1 (KIM-1) and osteopontin (OPN), while the effect of DOX was also analyzed in terms of changes in the anti-inflammatory cytokine, interleukin-10 (IL10). Of the oxidative stress induced genes analyzed, the expression of Gpx1 was found to be increased significantly. Significant increase was also observed in case of IL10 gene, while kidney injury biomarker level was not increased in response to DOX. It is concluded from this study that DOX treatment can modulate the expression levels of Gpx1 and IL10, while injury markers may have differential expression depending upon the duration following toxicity.
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