Characterization of the Renal Phenotype of Transgenic Rats Expressing the 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 pathophysiological interest because a long-term activated paracrine renal endothelin system has been impli...

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Bibliographic Details
Published in:Hypertension (Dallas, Tex. 1979) Tex. 1979), 1996-08, Vol.28 (2), p.196-201
Main Authors: Hocher, Berthold, Liefeldt, Lutz, Thone-Reineke, Christa, Orzechowski, Hans-Dieter, Distler, Armin, Bauer, Christian, Paul, Martin
Format: Article
Language:English
Subjects:
Animals
Animals, Genetically Modified
Base Sequence
Biological and medical sciences
Biotechnology
Blood Pressure - genetics
Disease Models, Animal
Endothelins - genetics
Female
Fundamental and applied biological sciences. Psychology
Gene Expression
Genetic engineering
Genetic technics
Humans
In Situ Hybridization
Kidney - pathology
Methods. Procedures. Technologies
Molecular Sequence Data
Phenotype
Polymerase Chain Reaction
Potassium - blood
Potassium - urine
Rats
Rats, Sprague-Dawley
Sclerosis
Sodium - blood
Sodium - urine
Transcription, Genetic
Transgenes
Transgenic animals
Transgenic animals and transgenic plants
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Summary: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 pathophysiological interest because a long-term activated paracrine renal endothelin system has been implicated in chronic renal failure due to progressive glomerular injury. Therefore, our aim in the present study was to analyze renal transgene expression in detail and address the question of whether transgene expression causes phenotypic and functional changes in 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 radioimmunoassay. For histological evaluation of renal tissue, all samples were subjected 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 gene was almost exclusively expressed within the glomeruli. The glomerular transgene expression resulted in a significantly increased glomerular injury score and likewise in a significantly increased protein excretion, whereas glomerular filtration rate was not altered. Blood pressure was similar in TGR(hET-2)37 rats and age-matched controls, suggesting 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 glomerulosclerosis with significantly increased protein excretion that is independent of blood pressure. We suggest that TGR(hET-2)37 rats are a new monogenetic animal model for study of the paracrine renal endothelin system and its involvement in renal pathophysiology. (Hypertension. 1996;28:196-201.)
ISSN:0194-911X
1524-4563
DOI:10.1161/01.HYP.28.2.196