A role of the (pro)renin receptor in neuronal cell differentiation

Abstract

The (pro)renin receptor [(P)RR] plays a pivotal role in the renin-angiotensin system. Experimental models emphasize the role of (P)RR in organ damage associated with hypertension and diabetes. However, a mutation of the (P)RR gene, resulting in frame deletion of exon 4 [⌬4-(P)RR] is associated with X-linked mental retardation (XLMR) and epilepsy pointing to a novel role of (P)RR in brain development and cognitive function. We have studied (P)RR expression in mouse brain, as well as the effect of transfection of ⌬4-(P)RR on neuronal differentiation of rat neuroendocrine PC-12 cells induced by nerve growth factor (NGF). In situ hybridization showed a wide distribution of (P)RR, including in key regions involved in the regulation of blood pressure and body fluid homeostasis. In mouse neurons, the receptor is on the plasma membrane and in synaptic vesicles, and stimulation by renin provokes ERK1/2 phosphorylation. In PC-12 cells, (P)RR localized mainly in the Golgi and in endoplasmic reticulum and redistributed to neurite projections during NGF-induced differentiation. In contrast, ⌬4-(P)RR remained cytosolic and inhibited NGF-induced neuronal differentiation and ERK1/2 activation. Cotransfection of PC-12 cells with (P)RR and ⌬4-(P)RR cDNA resulted in altered localization of (P)RR and inhibited (P)RR redistribution to neurite projections upon NGF stimulation. Furthermore, (P)RR dimerized with itself and with ⌬4-(P)RR, suggesting that the XLMR and epilepsy phenotype resulted from a dominant-negative effect of ⌬4-(P)RR, which coexists with normal transcript in affected males. In conclusion, our results show that (P)RR is expressed in mouse brain and suggest that the XLMR and epilepsy phenotype might result from a dominant-negative effect of the ⌬4-(P)RR protein.brain (P)RR expression; functional (P)RR; X-linked mental retardation THE CLASSICAL RENIN-ANGIOTENSIN system (RAS) is an intravascular enzymatic cascade that generates ANG II, considered the biologically active peptide, and plays a major role in the control of blood pressure, as well as fluid and salt balance. A receptor for renin and its proenzyme form, prorenin, called (pro)renin receptor [(P)RR] was recently cloned (20). The binding of renin and of prorenin results in increased angiotensin generation at the cell surface. Activation of (P)RR results in the activation of the MAP kinases ERK1/2 pathway and in upregulation of profibrotic genes, independently of ANG II generation (9, 10, 13, 21). These biochemical characteristics have generated a special interest in potential nonhemodynamic functions of renin ad prorenin. The receptor is abundantly expressed in adult human (20) and rat (14) organs, including the brain. Although overexpression of (P)RR is associated with a renal (15) and cardiovascular phenotype (3), it is surprising that alterations in the (P)RR gene, ATP6ap2 point to an essential role of (P)RR in cell survival and development of the central nervous system. In zebra fish, (P)RR/ATP6AP2 is expressed at a very early stage of development (www.zfin.o...

Prorenin, Renin, and Their Receptor

“…29 Natural mutations in (P)RR/ATP6AP2 in humans lead to mental retardation and epilepsy, 30 and the human mutation has been shown recently to act in a dominant-negative fashion to redirect (P)RR/ATP6AP2 in neuronal cells. 31 All of these findings are compatible with (P)RR/ATP6AP2 acting as a critical component of the v-Hϩ-ATPase. As such, it is probably time to acknowledge that (P)RR and ATP6AP2 are, in fact, the same protein and that the small amount of ATP6AP2 that makes it to the cell surface might bind renin and prorenin.…”

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

“…Chronic overexpression of this receptor in the SON alters body fluid homeostasis in normotensive rats, while genetic knockdown of the expression of SON PRR significantly attenuated the age-dependent blood pressure increase in the SHR (38), indicating hypothalamic PRR plays a critical role in the control of blood pressure. PRR is also highly expressed in the hypothalamic paraventricular nucleus (PVN) (7,38). The PVN is one of the most important brain areas controlling sympathetic outflow.…”

A map and new directions for the (pro)renin receptor in the brain: focus on “A role of the (pro)renin receptor in neuronal cell differentiation”

“…Importantly, in this paper, Contrepas et al (2), using in situ hybridization, show the presence of the (P)RR mRNA in various brain regions, some of them, like the subfornical organ (SFO), paraventricular nucleus, the supraoptic nucleus, the nucleus of the tractus solitarius (NTS), or the rostral ventrolateral medulla, being famous for their involvement in the central regulation of cardiovascular function and volume homeostasis. Of particular interest are the data showing that the (P)RR mRNA was highly expressed in the SFO and the NTS.…”