Obesity has been implicated in the development of many cancers. This can lead to genome damage, especially in the form of double-strand break, the presence of which is now easily detected through nuclear phosphorylation of histone H2AX (γ-H2AX) focus assay. Recently, the endothelin (ET) axis has also been shown to have a role in the growth and progression of several tumors, including lung cancer. The aim of this study was to evaluate the ET-1 system transcriptional alterations and γ-H2AX in lung tissue of Zucker rats subdivided into obese (O, n=22) and controls (CO, n=18) rats: under either fasting conditions (CO fc-O fc) or acute hyperglycemia (CO AH-O AH). Significantly higher prepro-ET-1 ( p=0.05) and ET-converting enzyme ( ECE)-2 mRNA expression was observed in O with respect to CO. A significant positive association was observed between prepro-ET-1 and ET-A in the whole rat population ( p=0.009) or in the obese group alone ( p=0.007). The levels of γ-H2AX in O and in O AH rats were significantly higher ( p=0.019) than in the corresponding CO and CO AH rats ( p=0.038). The study shows an inappropriate secretion of ET-1 in O animals with a parallel DNA damage in their lungs, providing novel mechanisms by which ET receptor antagonist may exert organ protection. [ABSTRACT FROM AUTHOR]