This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Background and Aims: The expression and activity of all of the enzymes required for aldosterone synthesis have been demonstrated in the rat and human brain. To study the potential role of centrally synthesized aldosterone in hypertension and target organ damage, we developed a transgenic rat (Syn1/AS-Tg rat) that over-expresses aldosterone synthase (AS) selectively in neurons. Methods: We generated our transgenic rat model by over-expressing the rat aldosterone synthase cDNA under the control of the rat synapsin-1 promoter (4.5 kbp) using lentiviral delivery to overcome the limitations of traditional transgenesis by naked DNA injection in rat embryos. Results: AS mRNA in the brain measured by real time RT-PCR was 100 times greater in Syn1/AS-Tg rats compared with WT rats (n=8). The blood pressure of the Syn1/AS-Tg on a standard rat chow, 0.28% salt, had significantly higher, 20 mmHg, mean arterial pressures both by tail cuff(n=11) and by indwelling catheter (n=4) in the conscious freely moving rat. Urinary aldosterone, an index of circulating aldosterone, was not different in Syn1/AS-Tg compared with WT rats (n=5), indicating that the amount of aldosterone produced by the transgene did not exceed that produced by the adrenal under control of the systemic RAS and that central increases in aldosterone alone lead to increased blood pressure in the Syn1/AS-Tg. At 13 weeks of age the Syn1/AS-Tg had significant cardiac hypertrophy, proteinuria, and renal collagen and TGF-beta as compared to WT controls. The few animals allowed to live past 12 months of age experienced severe congestive heart failure by 14 months of age.Conclusion: This novel and unique rat model will allow us to study the systemic effects of higher levels of aldosterone in neurons on the cardiovascular system without the direct of effects of aldosterone excess in peripheral organs.
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