Deletion of proton-sensing receptor GPR4 associates with lower blood pressure and lower binding of angiotensin II receptor in SFO

Abstract

Diets rich in grains and meat and low in fruits and vegetables (acid-producing diets) associate with incident hypertension, whereas vegetarian diets associate with lower blood pressure (BP). However, the pathways that sense and mediate the effects of acid-producing diets on BP are unknown. Here, we examined the impact of the deletion of an acid sensor GPR4 on BP. GPR4 is a proton-sensing G protein-coupled receptor and an acid sensor in brain, kidney, and blood vessels. We found that GPR4 mRNA was higher in subfornical organ (SFO) than other brain regions. GPR4 protein was abundant in SFO and present in capillaries throughout the brain. Since SFO partakes in BP regulation through the renin-angiotensin system (RAS), we measured BP in GPR4-/- and GPR4+/+ mice and found that GPR4 deletion associated with lower systolic BP: 87 ± 1 mmHg in GPR4-/- (n = 35) vs. 99 ± 2 mmHg (n = 29) in GPR4+/+; P < 0.0001, irrespective of age and sex. Angiotensin II receptors detected by I-Sarthran binding were lower in GPR4-/- than GPR4+/+ mice in SFO and in paraventricular nucleus of hypothalamus. Circulating angiotensin peptides were comparable in GPR4-/- and GPR4+/+ mice, as were water intake and excretion, serum and urine osmolality, and fractional excretion of sodium, potassium, or chloride. A mild metabolic acidosis present in GPR4-/- mice did not associate with elevated BP, implying that deficiency of GPR4 may preclude the effect of chronic acidosis on BP. Collectively, these results posit the acid sensor GPR4 as a novel component of central BP control through interactions with the RAS.

CNS distribution, signalling properties and central effects of G-protein coupled receptor 4

“…The cellular phenotype best established to be associated with strong GPR4 expression is endothelium in peripheral tissues as well as in the brain ( Huang et al., 2007 ; Kim et al., 2005 ; Qiao et al., 2006 ; Sun et al., 2016 ; Wyder et al., 2011 ), this being consistent with the published transcriptome data ( Zhang et al., 2014 , 2016 ). GPR4 activity in peripheral endothelial cells has been implicated in blood vessel formation ( Dong et al., 2013 ), transmigration of monocytes ( Huang et al., 2007 ), responses to vascular endothelial growth factor ( Wyder et al., 2011 ), vascular inflammation ( Dong et al., 2013 ) and endothelial adhesiveness ( Chen et al., 2011 ).…”

“…Previous work had established that, in peripheral tissues, GPR4 is prominently expressed in the endothelium of blood vessels ( Huang et al., 2007 ; Kim et al., 2005 ; Qiao et al., 2006 ; Wyder et al., 2011 ), where its deletion can cause major abnormalities ( Yang et al., 2007 ). In the brain, presence of GPR4 was confirmed for vascular endothelium ( Sun et al., 2016 ). In addition, transcriptome data unequivocally map GPR4 to endothelium with hardly any expression in other brain cell types, at least in front brain regions ( Zhang et al., 2014 , 2016 ).…”

“…Thus, there is a certain controversy regarding localization of GPR4 in the brain, especially given recent direct demonstration of GPR4 expression in the capillaries of at least some parts of the brain ( Sun et al., 2016 ) and images available in Allen brain atlas ( http://www.brain-map.org/ ).…”

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…AT 1 R in the SFO is also required to mediate a sustained elevation in blood pressure caused by intermittent hypoxia, a model of sleep apnea (921). Expression of AT 1 R in the SFO (and PVN) may be mediated by GRP4, which encodes a protonsensing receptor (1015). Because of the importance of ANG II in the SFO, the responses mediated by its signaling and the downstream pathways induced by ANG II has been the frequent topic of investigation.…”

GATA4 is a negative regulator of contractility in testicular peritubular myoid cells

“…Our study suggests that Ednrb is repressed by GATA4 in PTM cells; thus, the EDN1 (ligand)-EDNRB (receptor) signaling may be attenuated after GATA4 overexpression. Based on the RNA sequencing and qRT-PCR data, we suggest that GATA4 negatively regulates PTM cell contraction likely via both depressing the expression of Agt (encoding for angiotensinogen) and Ace (encoding for angiotensinconverting enzyme) and upregulating the level of Gpr4 that may be a reductor of angiotensin receptor affinity (Sanada et al 2016, Sun et al 2016. Angiotensin I (ANGI) is formed by the action of renin on AGT, and it is further converted to ANGII through removal of two C-terminal residues by the enzyme ACE (Welter et al 2014).…”