title: A genetically clamped renin transgene for the induction of hypertension.
abstract: Experimental analysis of the effects of individual components of complex mammalian systems is frequently impeded by compensatory adjustments that animals make to achieve homeostasis. We here introduce a genetic procedure for eliminating this type of impediment, by using as an example the development and testing of a transgene for "genetically clamping" the expression of renin, the major homeostatically responding component of the renin-angiotensin system, one of the most important regulators of blood pressure. To obtain a renin transgene whose expression is genetically clamped at a constant level, we have used single-copy chosen-site gene targeting to insert into a liver-specific locus a single copy of a modified mouse renin transgene driven by a liver-specific promoter/enhancer. The resulting transgene expresses renin ectopically at a constant high level in the liver and leads to elevated plasma levels of prorenin and active renin. The transgenic mice display high blood pressure, enhanced thirst, high urine output, proteinuria, and kidney damage. Treatment with the angiotensin II type I receptor antagonist, losartan, reduces the hypertension, albuminuria, and kidney damage, but does not affect expression of the transgene. This genetically clamped renin transgene can be used in models in which hypertension and its complications need to be investigated in a high prorenin/renin environment that is not subject to homeostatic compensations by the animal when other factors are changed.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Kathleen M I
authors.initials: KM
authors.lastname: Caron
authors.forename: Leighton R
authors.initials: LR
authors.lastname: James
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Scott G
authors.initials: SG
authors.lastname: Morham
authors.forename: Maria Luisa S
authors.initials: ML
authors.lastname: Sequeira Lopez
authors.forename: R Ariel
authors.initials: RA
authors.lastname: Gomez
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Reudelhuber
authors.forename: Oliver
authors.initials: O
authors.lastname: Smithies
mesh_terms: D000818:Animals; D001835:Body Weight; D017931:DNA Primers; D004742:Enhancer Elements, Genetic; D005813:Genes, Synthetic; D005838:Genotype; D006400:Hematocrit; D006973:Hypertension / Q000235:genetics*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012083:Renin / Q000097:blood / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012709:Serum Albumin / Q000235:genetics
chemical_list: D017931:DNA Primers; D012709:Serum Albumin; D012083:Renin