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.

Progressive Renal Disease Established by Renin-Coding Adeno-Associated Virus–Driven Hypertension in Diverse Diabetic Models

“…12 Increased ACR was detected after 2 weeks; however, a decline in ACR approaching baseline after 4 weeks of AngII infusion was observed, 12 suggesting loss of drug stability as a limiting factor of AngII infusion. 38 This study highlights the unique advantage of ReninAAV to reliably induce persistent hypertension required for the development of its complications in animal models.…”

“…ReninAAV and LacZAAV were obtained as previously described. 38 Mice received a single retro-orbital injection of ReninAAV (1310 10 or 5310 9 GC per animal; doses on the basis of previous studies) or LacZAAV at approximately 12 weeks of age. 38 The following parameters were monitored weekly for the first 4 weeks postinjection and Table 3.…”

“…38 Mice received a single retro-orbital injection of ReninAAV (1310 10 or 5310 9 GC per animal; doses on the basis of previous studies) or LacZAAV at approximately 12 weeks of age. 38 The following parameters were monitored weekly for the first 4 weeks postinjection and Table 3. Top ten up-and downregulated genes identified by microarray analysis of kidney tissue from ReninAAV db/db uNx and eNOS 2/2 db/db mice with matched serum creatinine values compared with LacZAAV db/db uNx and db/db mice, respectively: top genes changed in both ReninAAV db/db uNx and eNOS Genes were identified that were shared between the two models.…”

“…bimonthly for an additional 4-8 weeks (8-12 weeks total): body weight, ACR, and SAP (tail cuff) as previously described. 38 Mice were euthanized at 8-12 weeks postinjection, and kidney were collected and fixed in 10% neutral buffered formalin for histologic processing. Serum and plasma were collected at necropsy for measurement of serum creatinine (enzymatic creatinine using a protocol validated by HPLC), BUN, glucose, and plasma renin activity as previously described.…”

Chronic Hyperphosphatemia and Vascular Calcification Are Reduced by Stable Delivery of Soluble Klotho

“…Urine ACR was obtained through a spot urine collection over a 2-to 3-hour period and analyzed as previously described. 63 Cell Culture and In Vitro Functional Assays …”