OVEREXPRESSION OF INTEGRIN-ASSOCIATED PROTEIN (CD47) IN RAT-KIDNEY TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal prox imal tubular necrosis, a consequence of free radical-associated damage , that ultimately leads to a polycystic change of the renal cortex and a high incidence of renal cell carcinoma (RCC) in rodents. The differ ential display technique was used to search for inducible genes in the kidney of male Wistar rats treated with Fe-NTA and in the induced RCC s. Six fragments were selected that showed specific quantitative chang es in mRNA. Two of them exhibited similar patterns in northern blots a s well. One fragment showed a high homology (89%) to murine integrin-a ssociated protein (IAP; CD47). We thus cloned rat IAP cDNA including t he entire coding region for use in further analysis. Rat IAP cDNA show ed a 21-amino-acid deletion that was also observed in human, but not i n mouse. Northern blots revealed that IAP was consistently overexpress ed in non-tumorous parts of the kidney (2.4-fold increase, n = 9, P<0. 0001) as compared with matched controls 1 to 2 years after Fe-NTA trea tment. IAP overexpression of more than 2.9-fold was found in 25% (2/8) of RCCs studied, and was limited to cases of a high histological grad e and lung metastasis. Unexpectedly, IAP expression was higher in the non-tumorous part of the kidney after Fe-NTA treatment (2.8-fold) than in RCC (1.5-fold) in each case (n = 4, P < 0.05). Abundant expression of IAP mRNA in the renal tubular epithelium after Fe-NTA treatment an d RCC cells was observed by in situ hybridization. The results suggest that IAP overexpression may be associated with Fe-NTA-induced renal c ortical tubular damage and regeneration that lead to a polycystic stat e, and with tumor progression and metastasis of the induced RCCs.