A role of the (pro) renin receptor in neuronal cell differentiation.
The (pro)renin receptor [(P)RR] plays pivotal role in the renin angiotensin system and although experimental models emphasize the role of (P)RR in fibrosis , in organ damage associated with hypertension and diabetes, a mutation of the (P)RR gene resulting in a truncated Delta4-(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. Our aims were to study (P)RR expression in mouse brain and the effect of transfection of Delta4-(P)RR on neuronal differentiation of PC-12 cells induced by nerve growth factor (NGF). In situ hybridization showed the expression of (P)RR in cortical neurons, pyramidal cells and thalamic relay nuclei. In mouse neurons the receptor is found on plasma membrane and in synaptic vesicles and stimulation by renin provoked ERK1/2 phosphorylation. In PC-12 cells, (P)RR localized mainly in the endoplasmic reticulum and redistributed to neurite projections when cells were induced to differentiate by NGF. In contrast, Delta4-(P)RR remained cytosolic and inhibited NGF-induced neuronal differentiation and ERK1/2 activation. Co-transfection of PC-12 with (P)RR and Delta4-(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 Delta4-(P)RR suggesting that the XLMR and epilepsy phenotype resulted from a dominant negative effect of Delta4-(P)RR. In conclusion, our results show that (P)RR is expressed in mouse brain where it may have a role in neuronal cell differentiation and suggest that the XLMR and epilepsy phenotype resulted from a dominant negative effect of the Delta4-(P)RR protein. Key words: (pro)renin receptor, neuronal cell differentiation.
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