Pathological significance of oxidative stress and its application to pathologic diagnosis

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Ferric nitrilotriacetate (Fe-NTA) induces oxidative renal damage leading to a high incidence of renal cell carcinoma (RCC) in rats. Differential display analysis of such RCCs revealed elevated expression of annexin 2 (Anx2), a substrate for kinases and a receptor for tissue-type plasminogen adivator and plasminogen. We conducted this study to clarifythe significance of Anx2 in Fenton reaction-based carcinogenesis. Messenger RNA and protein levels of Anx2 were increased time-dependently in the rat kidney after Fe-NTA administration as well as in LLC-PK1 cells after exposure to H_2O_2. The latter was inhibited by pretreatment with N-acetylcysteine, pyrrolidine dithiocarbamate or catalase. immunohistochemistry revealed negligible staining in the normal renal proximal tubules, but strong staining in regenerating proximal tubules, karyomegalic cells and RCCs. Metastasizing RCCs showed higher Anx2 protein levels. Anx2 was phosphorylated at serine and tyrosine residues in these cells and coim … More munoprecipitated with phosphorylated actin. Overexpresison of Anx2 induced a higher cell proliferation rate in LLC-PKI cells. In contrast, a decrease in proliferation leading to apoptosis was observed after Anx2 antisense treatment to cell lines established from Fe-NIA-induced RCCs. These results suggest that Anx2 is regulated by redox status, and that persistent operation of this adaptive mechanism plays a role in the proliferation and metastasis of oxidative stress-induced cancer. Furthermore, we demonstrated that peptide nucleic acid (PNA)-based mRNA in situ hybridization is applicable to paraffin-embedded pathologic specimens produced 50 years ago. We have developed an extremely rapid method for Western blot analysis by the use of low dose of microwave radiation. Finally, we have produced diagnostic criteria for the early humoral rejection in ABO-incompatible liver transplantation. This would be important for investigating the involvement of oxidative stress in the rejection of transplanted liver. Less