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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/R250    most recent 90832.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Contrepas, A. Articles by Nguyen, G. PubMed PubMed Citation Articles by Contrepas, A. Articles by Nguyen, G.

ARTICLES

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

Aurelie Contrepas,^1,* Joy Walker,^2,* Annette Koulakoff,³ Karl J. Franek,² Fatimunnisa Qadri,⁴ Christian Giaume,³ Pierre Corvol,¹ Charles E. Schwartz,^2, and Genevieve Nguyen^1,

¹Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 833 and Collège de France, Experimental Medicine Unit, Paris, France; ²Center for Molecular Studies, J. C. Self Research Institute, Greenwood Genetic Center, Greenwood, South Carolina; ³INSERM, Unit 840, Collège de France, Paris, France; and ⁴Experimental and Clinical Research Center, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

Submitted 14 October 2008 ; accepted in final form 19 May 2009

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

This article has been cited by other articles:

				E. Lazartigues 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" Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2009; 297(2): R248 - R249. [Full Text] [PDF]