Abstract
Objective: The blood-brain-barrier limits the traffic of all components of the renin-angiotensin system. Brain-localized production of angiotensin II (Ang II) has been challenged because the rate-limiting enzyme, renin, is expressed at very low levels in the brain. Our group has developed a transgenic mouse line that selectively overexpresses rat angiotensinogen (Agt) in brain astrocytes (Agt-Tg) yielding detectable levels of Ang II. Design and method: To confirm that Ang II is locally produced in the brain, the endogenous mouse Agt gene was deleted from Agt-Tg (Agt-Tg/Agt-KO) by breeding Agt-Tg with Agt-deficient mice (Agt-KO). To determine if renin is involved in the local production of Ang II in the brain, the genes (Ren1d and Ren2) encoding for renin of Agt-Tg were genetically deleted by crossbreeding with renin-deficient mice (Ren-KO). The resulting mouse line overexpresses Agt specifically in the brain but globally lacks renin (Agt-Tg/Ren-KO). All lines were backcrossed to the FVB/N inbred background for at least 8 generations. Whole brains and blood were collected from males and females aging between 15-22 weeks. Angiotensin peptides (Ang I, Ang II, Ang III and Ang 1-7) were quantified using LC-MS/MS by Attoquant Diagnostics GmbH Results: Ang II was detected in the brain, but not in the blood of Agt-Tg/Agt-KO mice suggesting local synthesis. Interestingly, Ang II was not detectable in brain samples of Agt-Tg/Ren-KO in contrast to their littermates Agt-Tg indicating that renin is essential for brain Agt processing into Ang II. Moreover, Ang I, Ang II were not detected in the blood of Agt-Tg/Ren-KO as expected but detectable in Agt-Tg. Finally, FVB/N wildtype controls presented no detectable levels angiotensin peptides in brain samples but in the blood. Conclusions: Collectively, the results from mice with brain-specific Agt overexpression support the notion that the brain locally and renin-dependently produces Ang II. The specific involvement of central or peripheral renin remains to be determined.
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