title: Viral transduction of renin rapidly establishes persistent hypertension in diverse murine strains.
abstract: Mice provide a unique platform to dissect disease pathogenesis, with the availability of recombinant inbred strains and diverse genetically modified strains. Leveraging these reagents to elucidate the mechanisms of hypertensive tissue injury has been hindered by difficulty establishing persistent hypertension in these inbred lines. ANG II infusion provides relatively short-term activation of the renin-angiotensinogen system (RAS) with concomitant elevated arterial pressure. Longer-duration studies using renin transgenic mice are powerful models of chronic hypertension, yet are limited by the genetic background on which the transgene exists and the exposure throughout development. The present studies characterized hypertension produced by transduction with a renin-coding adeno-associated virus (ReninAAV). ReninAAV mice experienced elevated circulating renin with concurrent elevations in arterial pressure. Following a single injection of ReninAAV, arterial pressure increased on average +56 mmHg, an increase that persisted for at least 12 wk in three distinct and widely used strains of adult mice: 129/S6, C56BL/6, and DBA/2J. This was accomplished without surgical implantation of pumps or complex breeding and backcrossing. In addition, ReninAAV mice developed pathophysiological changes associated with chronic hypertension, including increased heart weight and albuminuria. Thus ReninAAV provides a unique tool to study the onset of and effects of persistent hypertension in diverse murine models. This model should facilitate our understanding of the pathogenesis of hypertensive injury.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Harlan
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ostroski
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Tamer
authors.initials: T
authors.lastname: Coskun
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Loudon D
authors.initials: LD
authors.lastname: Yantis
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana jheuer@lilly.com.
authors.forename: Josef G
authors.initials: JG
authors.lastname: Heuer
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000378:metabolism; D000818:Animals; D062186:Arterial Pressure / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D005822:Genetic Vectors; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009154:Mutation; D010641:Phenotype; D012083:Renin / Q000096:biosynthesis* / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics; D013997:Time Factors; D014161:Transduction, Genetic
chemical_list: D012083:Renin
keywords: adenovirus; hypertensive murine model; renin