Renin-a in the Subfornical Organ Plays a Critical Role in the Maintenance of Salt-Sensitive Hypertension
The brain renin-angiotensin system plays important roles in blood pressure and cardiovascular regulation. There are two isoforms of prorenin in the brain: the classic secreted form (prorenin/sREN) encoded by renin-a, and an intracellular form (icREN) encoded by renin-b. Emerging evidence indicates t...
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/9/1169 |
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| author | Silvana G. Cooper Lucas A. C. Souza Caleb J. Worker Ariana Julia B. Gayban Sophie Buller Ryosuke Satou Yumei Feng Earley |
| author_facet | Silvana G. Cooper Lucas A. C. Souza Caleb J. Worker Ariana Julia B. Gayban Sophie Buller Ryosuke Satou Yumei Feng Earley |
| author_sort | Silvana G. Cooper |
| collection | DOAJ |
| description | The brain renin-angiotensin system plays important roles in blood pressure and cardiovascular regulation. There are two isoforms of prorenin in the brain: the classic secreted form (prorenin/sREN) encoded by renin-a, and an intracellular form (icREN) encoded by renin-b. Emerging evidence indicates the importance of renin-b in cardiovascular and metabolic regulation. However, the role of endogenous brain prorenin in the development of salt-sensitive hypertension remains undefined. In this study, we test the hypothesis that renin-a produced locally in the brain contributes to the pathogenesis of hypertension. Using RNAscope, we report for the first time that renin mRNA is expressed in several regions of the brain, including the subfornical organ (SFO), the paraventricular nucleus of the hypothalamus (PVN), and the brainstem, where it is found in glutamatergic, GABAergic, cholinergic, and tyrosine hydroxylase-positive neurons. Notably, we found that renin mRNA was significantly elevated in the SFO and PVN in a mouse model of DOCA-salt–induced hypertension. To examine the functional importance of renin-a in the SFO, we selectively ablated renin-a in the SFO in renin-a–floxed mice using a Cre-lox strategy. Importantly, renin-a ablation in the SFO attenuated the maintenance of DOCA-salt–induced hypertension and improved autonomic function without affecting fluid or sodium intake. Molecularly, ablation of renin-a prevented the DOCA-salt–induced elevation in NADPH oxidase 2 (NOX2) in the SFO without affecting NOX4 or angiotensin II type 1 and 2 receptors. Collectively, our findings demonstrate that endogenous renin-a within the SFO is important for the pathogenesis of salt-sensitive hypertension. |
| first_indexed | 2024-03-10T00:37:23Z |
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| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T00:37:23Z |
| publishDate | 2022-08-01 |
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| series | Biomolecules |
| spelling | doaj.art-7fc706531b3a47a5a6fedc5d705e92082023-11-23T15:14:03ZengMDPI AGBiomolecules2218-273X2022-08-01129116910.3390/biom12091169Renin-a in the Subfornical Organ Plays a Critical Role in the Maintenance of Salt-Sensitive HypertensionSilvana G. Cooper0Lucas A. C. Souza1Caleb J. Worker2Ariana Julia B. Gayban3Sophie Buller4Ryosuke Satou5Yumei Feng Earley6Departments of Pharmacology, and Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, NV 89557, USADepartments of Pharmacology, and Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, NV 89557, USADepartments of Pharmacology, and Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, NV 89557, USADepartments of Pharmacology, and Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, NV 89557, USAMRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 1TN, UKDepartment of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USADepartments of Pharmacology, and Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, NV 89557, USAThe brain renin-angiotensin system plays important roles in blood pressure and cardiovascular regulation. There are two isoforms of prorenin in the brain: the classic secreted form (prorenin/sREN) encoded by renin-a, and an intracellular form (icREN) encoded by renin-b. Emerging evidence indicates the importance of renin-b in cardiovascular and metabolic regulation. However, the role of endogenous brain prorenin in the development of salt-sensitive hypertension remains undefined. In this study, we test the hypothesis that renin-a produced locally in the brain contributes to the pathogenesis of hypertension. Using RNAscope, we report for the first time that renin mRNA is expressed in several regions of the brain, including the subfornical organ (SFO), the paraventricular nucleus of the hypothalamus (PVN), and the brainstem, where it is found in glutamatergic, GABAergic, cholinergic, and tyrosine hydroxylase-positive neurons. Notably, we found that renin mRNA was significantly elevated in the SFO and PVN in a mouse model of DOCA-salt–induced hypertension. To examine the functional importance of renin-a in the SFO, we selectively ablated renin-a in the SFO in renin-a–floxed mice using a Cre-lox strategy. Importantly, renin-a ablation in the SFO attenuated the maintenance of DOCA-salt–induced hypertension and improved autonomic function without affecting fluid or sodium intake. Molecularly, ablation of renin-a prevented the DOCA-salt–induced elevation in NADPH oxidase 2 (NOX2) in the SFO without affecting NOX4 or angiotensin II type 1 and 2 receptors. Collectively, our findings demonstrate that endogenous renin-a within the SFO is important for the pathogenesis of salt-sensitive hypertension.https://www.mdpi.com/2218-273X/12/9/1169renin-angiotensin systemsalt-sensitive hypertensionNAD(P)H oxidaseangiotensin receptorautonomic control |
| spellingShingle | Silvana G. Cooper Lucas A. C. Souza Caleb J. Worker Ariana Julia B. Gayban Sophie Buller Ryosuke Satou Yumei Feng Earley Renin-a in the Subfornical Organ Plays a Critical Role in the Maintenance of Salt-Sensitive Hypertension Biomolecules renin-angiotensin system salt-sensitive hypertension NAD(P)H oxidase angiotensin receptor autonomic control |
| title | Renin-a in the Subfornical Organ Plays a Critical Role in the Maintenance of Salt-Sensitive Hypertension |
| title_full | Renin-a in the Subfornical Organ Plays a Critical Role in the Maintenance of Salt-Sensitive Hypertension |
| title_fullStr | Renin-a in the Subfornical Organ Plays a Critical Role in the Maintenance of Salt-Sensitive Hypertension |
| title_full_unstemmed | Renin-a in the Subfornical Organ Plays a Critical Role in the Maintenance of Salt-Sensitive Hypertension |
| title_short | Renin-a in the Subfornical Organ Plays a Critical Role in the Maintenance of Salt-Sensitive Hypertension |
| title_sort | renin a in the subfornical organ plays a critical role in the maintenance of salt sensitive hypertension |
| topic | renin-angiotensin system salt-sensitive hypertension NAD(P)H oxidase angiotensin receptor autonomic control |
| url | https://www.mdpi.com/2218-273X/12/9/1169 |
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