No evidence for brain renin-angiotensin system activation during DOCA-salt hypertension

Estrellita Uijl, Liwei Ren, KMM Colafella, Richard van Veghel, Ingrid Van den Berg - Garrelds, O Domenig, M Poglitsch, I Zlatev, JB Kim, S Huang, L Melton, Ewout Hoorn, D Foster, AHJ Danser

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Scopus)

Abstract

Brain renin–angiotensin system (RAS) activation is thought to mediate deoxycorticosterone acetate (DOCA)-salt hypertension, an animal model for human primary hyperaldosteronism. Here, we determined whether brainstem angiotensin II is generated from locally synthesized angiotensinogen and mediates DOCA-salt hypertension. To this end, chronic DOCA-salt-hypertensive rats were treated with liver-directed siRNA targeted to angiotensinogen, the angiotensin II type 1 receptor antagonist valsartan, or the mineralocorticoid receptor antagonist spironolactone (n = 6–8/group). We quantified circulating angiotensinogen and renin by enzyme-kinetic assay, tissue angiotensinogen by Western blotting, and angiotensin metabolites by LC-MS/MS. In rats without DOCA-salt, circulating angiotensin II was detected in all rats, whereas brainstem angiotensin II was detected in 5 out of 7 rats. DOCA-salt increased mean arterial pressure by 19 + 1 mmHg and suppressed circulating renin and angiotensin II by >90%, while brainstem angiotensin II became undetectable in 5 out of 7 rats (<6 fmol/g). Gene silencing of liver angiotensinogen using siRNA lowered circulating angiotensinogen by 97 + 0.3%, and made brainstem angiotensin II undetectable in all rats (P<0.05 vs. non-DOCA-salt), although brainstem angiotensinogen remained intact. As expected for this model, neither siRNA nor valsartan attenuated the hypertensive response to DOCA-salt, whereas spironolactone normalized blood pressure and restored brain angiotensin II together with circulating renin and angiotensin II. In conclusion, despite local synthesis of angiotensinogen in the brain, brain angiotensin II depended on circulating angiotensinogen. That DOCA-salt suppressed circulating and brain angiotensin II in parallel, while spironolactone simultaneously increased brain angiotensin II and lowered blood pressure, indicates that DOCA-salt hypertension is not mediated by brain RAS activation.

Original languageEnglish
Pages (from-to)259-274
Number of pages16
JournalClinical Science
Volume135
Issue number2
DOIs
Publication statusPublished - 22 Jan 2021

Bibliographical note

Funding Information:
This work was partially supported by Alnylam Pharmaceuticals. K.M.MC. was supported by a National Health and Medical Research Council of Australia CJ Martin Fellowship [grant number 1112125]. L.R. was supported by a National Natural Science Foundation of China [grant number 81900668].

Publisher Copyright:
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society

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