CHARACTERIZATION OF THE RENAL PHENOTYPE OF TRANSGENIC RATS EXPRESSINGTHE HUMAN ENDOTHELIN-2 GENE

We have previously established a transgenic rat model termed TGR(hET-2 )37 overexpressing the human endothelin-2 (ET-2) gene with high renal transgene expression. This renal overexpression is of pathophysiologic al interest because a long-term activated paracrine renal endothelin s ystem has been implicated in chronic renal failure due to progressive glomerular injury. Therefore, our aim in the present study was to anal yze renal transgene expression in detail and address the question of w hether transgene expression causes phenotypic and functional changes i n the kidney. We used reverse transcription-polymerase chain reaction and in situ hybridization techniques for transgene expression analysis . Tissue ET-2 concentrations were measured with a specific radioimmuno assay. For histological evaluation of renal tissue, all samples were s ubjected to hematoxylin-eosin and periodic acid-Schiff staining. Renal tissue ET-2 concentrations were significantly increased in TGR(hET-2) 37 rats. Using in situ hybridization, we found that the human ET-2 gen e was almost exclusively expressed within the glomeruli. The glomerula r transgene expression resulted in a significantly increased glomerula r injury score and likewise in a significantly increased protein excre tion, whereas glomerular filtration rate was not altered. Blood pressu re was similar in TGR(hET-2)37 rats and age-matched controls, suggesti ng that the local changes in the kidney were correlated with paracrine endothelin actions. In conclusion, our study revealed that the major renal expression site of the human ET-2 transgene in TGR(hET-2)37 rats was within the glomeruli and caused the development of glomeruloscler osis with significantly increased protein excretion that is independen t of blood pressure. We suggest that TGR(hET-2)37 rats are a new monog enetic animal model for study of the paracrine renal endothelin system and its involvement in renal pathophysiology.