Transforming Growth Factor‐α Expression of Renal Proximal Tubules in Wistar Rats Treated with Ferric and Aluminum Nitrilotriacetate

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Abstract
A high incidence of renal adenocarcinoma has been observed in rats treated with ferric nitrilotriacetate (Fe‐NTA) but not in rats treated with aluminum nitrilotriacetate (Al‐NTA). Transforming growth factor (TGF)‐α is one of the several cytokines that is known to be expressed in human and rat renal adenocarcinomas. However, its role in neoplastic transformation is still questionable. Therefore, we investigated the effect of repeated Fe‐NTA and Al‐NTA administration on renal TGF‐α expression. Male Wistar rats were given Fe‐NTA (n = 16, 5–10 mg FeAg) and Al‐NTA (n = 19, 1–2 mg Al/kg) i.p., three times a week for 3 or 12 weeks. Another group of rats (n=4) was given Fe‐NTA (5–10 mg FeAg) three times a week for 12 weeks and then left untreated for one year. Immunoreactivity for TGF‐α was positive in the collecting ducts and on the apical surface of proximal tubules in the outer stripe of the outer medulla in all the animals including NTA‐injected control animals. However, TGF‐α immunoreactivity in the regenerative proximal tubular epithelium was observed only in the animals treated with Fe‐NTA for 12 weeks. Northern blot analysis also showed expression of TGF‐α mRNA only in animals treated with Fe‐NTA for 12 weeks. The expression of TGF‐α mRNA in the kidney was stronger than that in the liver or brain, TGF‐α was also positive in renal cell carcinoma found in animals treated with Fe‐NTA for 12 weeks and left untreated for one year. These results suggest that TGF‐α expression may play an important role in renal carcinogenesis and that it may be a sensitive marker during the induction stage of renal cell carcinoma.