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Deletion of Secreted Form of Prorenin in the Subfornical Organ Attenuates the Development of DOCA‐salt‐induced Hypertension
Author(s) -
Cooper Silvana,
Souza Lucas,
Worker Caleb,
Feng Yumei
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02116
Subject(s) - subfornical organ , circumventricular organs , medicine , endocrinology , renin–angiotensin system , in situ hybridization , lamina terminalis , hypothalamus , astrocyte , immunolabeling , homeostasis , receptor , central nervous system , supraoptic nucleus , biology , blood pressure , messenger rna , immunohistochemistry , biochemistry , gene
We and others previously reported that the (pro)renin receptor (PRR) is important for the development and maintenance of hypertension. Renin and prorenin are endogenous ligand for the PRR. In the central nervous system, no renin activity was detected; on the other hand, there are two isoforms of prorenin expressed in the brain; a secreted form of prorenin (sProrenin), encoded by renin‐a, and an intracellular form of prorenin (icProrenin), encoded by renin‐b. However, the role of sProrenin in the development of hypertension and whether it is locally synthesized inside the brain remains not clearly understood. Using RNAscope in situ hybridization, we report here that renin mRNA is present in the brain including the subfornical organ (SFO), paraventricular nucleus of hypothalamus, and brainstem. These finding were confirmed at protein level by immunolabeling using an antibody specific for sProrenin. In addition, we found that sProrenin immunoreactivity was co‐localized with neuronal marker NeuN, but not with the markers of astrocyte (GFAP) or microglia (IBA1). More importantly, in a deoxycorticosterone acetate (DOCA)‐salt‐induced hypertension model, we found a significant increase in sProrenin immunoreactivity in the SFO (fold change: 2.93 ± 0.34 vs. 1.00 ± 0.48; P = 0.009) when compared with the SHAM mice (n=4/group). The SFO is a vital circumventricular organ of the brain responsible for blood pressure (BP) regulation and body fluid homeostasis. Accordingly, we hypothesize that sProrenin locally produced in the SFO contributes to hypertension development. To test this hypothesis, we use adeno‐associated virus serotype 2 (AAV2) mediated Cre recombinase expression to selectively knock down sProrenin, but not icProrenin, in the sProrenin‐floxed mice exclusively in the SFO by microinjections of either control AAV virus (AAV2‐eGFP) or AAV2‐Cre‐eGFP. Two weeks prior to injection, telemetric transmitters were implanted into the carotid artery and mice were allowed to recover for BP recording in conscious free moving state. One week following AAV2 injection, mice were given DOCA‐salt (2.5mg/g DOCA, 0.9% NaCl in drinking water) for 3 weeks. At the end of protocol, sProrenin knock down in the SFO attenuated the development of DOCA‐salt‐induced hypertension (Mean arterial pressure: 102 ± 2 mmHg vs. 137 ± 6 mmHg, P ˂ 0.0001, n = 9/group) without affecting the saline fluid intake. In addition, BP response to chlorisondamine, an indicator of neurogenic contribution to blood pressure, was significantly lower in the SFO‐sProrenin deletion mice compared with the control group (ΔBP: ‐48± 4 mmHg v. ‐63± 3 mmHg, P = 0.0342, n = 9/group). In summary, our data demonstrates that sProrenin produced locally within the SFO is important for neural regulation of BP and contributes to the pathogenesis of neurogenic hypertension.