Nucleus of the Solitary Tract (Pro)Renin Receptor-Mediated Antihypertensive Effect Involves Nuclear Factor-κB-Cytokine Signaling in the Spontaneously Hypertensive Rat

Abstract

622( P ro)renin receptor (PRR) is highly expressed in many tissues, including those of the heart and brain, 1,2 and plays an important role in the maintenance of cardiovascular homeostasis in the periphery. 3,4 However, the role of PRR in the brain remains poorly understood. Despite intrinsically low renin concentrations in the brain, the ability of renin to signal in a similar manner to angiotensin (Ang)-II, 5 coupled with the presence of PRR in the brain cardioregulatory areas, 2,6 suggests a role for PRR in central cardiovascular control. Our previous study revealed that PRR expression is significantly increased in the nucleus of the solitary tract (NTS) and the supraoptic nucleus (SON) of spontaneously hypertensive rats (SHR) compared with normotensive Wistar Kyoto (WKY) controls. 6 Genetic knockdown of PRR in the SHR SON 6 and other cardioregulatory regions, such as the subfornical organ (SFO) 7 in hypertensive rats, resulted in a reduction of blood pressure (BP). However, the role of NTS PRR in BP control and its precise mechanisms remain elusive.Our interest in the role of NTS PRR derives from the following: (1) The NTS is the central termination site of baroreceptor input, regulating both the set-point of arterial pressure and the gain of the baroreflex, mechanisms essential for short-and long-term homeostatic control of arterial pressure 8,9 ; (2) In the hypertensive model, the NTS exhibits an abnormal inflammatory state because the expression of many inflammatory mediators known to be involved in modulating synaptic transmission, including interleukin (IL)-6 and C-C motif ligand 5 (Ccl5), are downregulated in the SHR NTS compared with the WKY rats 10,11 ; and (3) PRR mRNA in the SHR NTS is significantly increased compared with the WKY rats. 6 We propose that altered activity of PRR in the NTS is linked to hypertension, and that the NTS PRR regulates BP Abstract-The importance of the (pro)renin receptor (PRR) in the function of the central nervous system is increasingly evident because PRR seems to play a role in neuronal control of cardiovascular function. PRR expression is elevated in the nucleus of the solitary tract (NTS) of spontaneously hypertensive rats (SHR).In this study, we tested the hypothesis that altered activity of PRR in the NTS is linked to hypertension. Eight weeks of chronic knockdown of the NTS PRR, using recombinant adeno-associated virus type 2 (AAV2)-PRR-small hairpain RNA (shRNA)-mediated gene transduction, caused a significant increase in mean arterial pressure (MAP) in the SHR (shRNA, 173±5; Control, 151±6 mm Hg) but not in Wistar Kyoto rats (shRNA, 108±7; Control, 106±6 mm Hg). The MAP elevation in the SHR was associated with decreased inflammatory markers tumor necrosis factor-α, interleukin-6, C-C motif ligand 5, and their transcription factor, nuclear factor-κB. Consistent with the pressor effects of the PRR knockdown, acute bilateral NTS injection of human renin (2 pmol/side) decreased MAP and heart rate (HR) in SHR (ΔMAP, −38±4 mm Hg; Δheart rate, −40±10 bp...

Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats

“…Multiple factors affect sympathetic outflow such as sodium, ANG II, glutamate, cytokines, oxidative stress, and nitric oxide (NO) (11,12,34,41,47). Previous studies have demonstrated that brain PRR activation can increase the production of inflammatory cytokines, oxidative stress, and ANG II (32,37,46). Based on these observations, we speculate that activation of PVN PRR may be involved in increased sympathetic outflow.…”

“…Therefore, it is possible that sympathoexcitation elicited by activation of PRR in the PVN might not be sufficient to elevate ABP in normotensive animals. It would be expected that microinjection of prorenin into the PVN of hypertensive animals could induce sympathoexcitation and presser responses in a greater degree since their PRR expression is upregulated (22,38,46). Whether upregulation of PRR expression in hypertensive animals is able to enhance sympathoexcitation and induce a pressor response remains to be studied in the future.…”

“…ACCUMULATING EVIDENCE INDICATES that alteration of central (pro)renin receptor (PRR) is involved in the development of cardiovascular diseases including neurogenic hypertension (32,46). The importance of the brain PRR in cardiovascular control is further strengthened by the observation that increased PRR expression in brain cardiovascular control areas altered body fluid homeostasis (38) and genetic knockdown of the PRR induced long-term depressor effects in hypertensive animals (21,22,38).…”

“…Immunofluorescence staining of PRR was performed as described previously (38,46). Briefly, 10 m of brain sections containing the PVN from male adult SD rats were submerged in Ϫ20°C acetone for 5 min, followed by washing with TBS for another 5 min.…”

“…Binding of prorenin to the PRR leads to nonproteolytic activation of prorenin and mediates local ANG II formation (28). In addition, the PRR-(pro)renin complex stimulates a variety of signal transduction pathways independent of ANG II (8,28,46). Our previous study has shown that PRR is highly expressed in the brain cardiovascular control areas such as the hypothalamic supraoptic nucleus (SON), and its expression is significantly increased in the spontaneous hypertensive rat (SHR) compared with normotensive Wistar-Kyoto (WKY) controls (38).…”