Increased (pro)renin receptor expression in the subfornical organ of hypertensive humans

Abstract

The central nervous system plays an important role in essential hypertension in humans and in animal models of hypertension through modulation of sympathetic activity and Na⁺ and body fluid homeostasis. Data from animal models of hypertension suggest that the renin-angiotensin system in the subfornical organ (SFO) of the brain is critical for hypertension development. We recently reported that the brain (pro)renin receptor (PRR) is a novel component of the brain renin-angiotensin system and could be a key initiator of the pathogenesis of hypertension. Here, we examined the expression level and cellular distribution of PRR in the SFO of postmortem human brains to assess its association with the pathogenesis of human hypertension. Postmortem SFO tissues were collected from hypertensive and normotensive human subjects. Immunolabeling for the PRR and a retrospective analysis of clinical data were performed. We found that human PRR was prominently expressed in most neurons and microglia, but not in astrocytes, in the SFO. Importantly, PRR levels in the SFO were elevated in hypertensive subjects. Moreover, PRR immunoreactivity was significantly correlated with systolic blood pressure but not body weight, age, or diastolic blood pressure. Interestingly, this correlation was independent of antihypertensive drug therapy. Our data indicate that PRR in the SFO may be a key molecular player in the pathogenesis of human hypertension and, as such, could be an important focus of efforts to understand the neurogenic origin of hypertension. NEW & NOTEWORTHY This study provides evidence that, in the subfornical organ of the human brain, the (pro)renin receptor is expressed in neurons and microglia cells but not in astrocytes. More importantly, (pro)renin receptor immunoreactivity in the subfornical organ is increased in hypertensive humans and is significantly correlated with systolic blood pressure.

Keywords: (pro)renin receptor; brain; hypertension; renin-angiotensin system; subfornical organ.

Fig. 1.

Expression of the (pro)renin receptor (PRR) in subfornical organ (SFO) neurons of the human brain. A and B: SFO tissues were double immunolabeled for PRR (red) and neuronal marker microtubule-associated protein 2 (MAP2; green), astrocyte marker glial fibrillary acidic protein (GFAP; green), or microglial marker Iba1 (green). In B, white arrows indicate colocalization of PRR with MAP2 and Iba1. C: control sections without primary antibody and Alexa 488 (green)- or Alexa 594 (red)-labeled secondary antibody.

Fig. 2.

Elevated systolic blood pressure (SBP) in hypertensive subjects that had undergone antihypertensive drug treatment. Data from normotensive (NTN) subjects are in blue, and those from hypertensive (HTN) patients are in red. A: SBP in NTN and HTN groups. B: diastolic blood pressure (DBP) in NTN and HTN groups. C: age of study subjects. D: body mass index (BMI). E: correlation of age with SBP. F: correlation of BMI with SBP.

Fig. 3.

Increased (pro)renin receptor (PRR) expression levels in the subfornical organ (SFO) of the hypertensive human brain. A: representative image of SFO tissue immunolabeled with rabbit preimmune serum. B: representative image of a normotensive (NTN) human SFO immunolabeled for PRR. C: representative image of a hypertensive (HTN) SFO immunolabeled for PRR. D: relative intensity of PRR immunoreactivity in NTN and HTN groups. E: relative intensity of PRR immunoreactivity in NTN and HTN subjects, subdivided into groups that received renin-angiotensin system blockers (RASBs) or other antihypertensive drugs (HTN Others). F: SBP of NTN and HTN subjects, subdivided into groups that received RASBs or HTN Others. AU, arbitrary units.

Fig. 4.

(Pro)renin receptor (PRR) immunoreactivity is positively correlated with systolic blood pressure (SBP). A−D: correlation of the relative intensity of PRR immunoreactivity with SBP (A), diastolic blood pressure (DBP; B), age (C), and body mass index (BMI; D).