Sorting nexin 1 loss results in D₅ dopamine receptor dysfunction in human renal proximal tubule cells and hypertension in mice

Authors

Van Anthony M. Villar, Children's Research Institute, Children's National Medical Center
John Edward Jones, Children's Research Institute, Children's National Medical Center
Ines Armando, Children's Research Institute, Children's National Medical Center
Laureano D. Asico, Children's Research Institute, Children's National Medical Center
Crisanto S. Escano, Children's Research Institute, Children's National Medical Center
Hewang Lee, Children's Research Institute, Children's National Medical Center
Xiaoyan Wang, Children's Research Institute, Children's National Medical Center
Yu Yang, Children's Research Institute, Children's National Medical Center
Annabelle M. Pascua-Crusan, Children's Research Institute, Children's National Medical Center
Cynthia P. Palmes-Saloma, Children's Research Institute, Children's National Medical Center
Robin A. Felder, University of Virginia School of Medicine
Pedro A. Jose, Children's Research Institute, Children's National Medical Center

Document Type

Journal Article

Publication Date

1-4-2013

Journal

Journal of Biological Chemistry

Volume

288

Issue

1

DOI

10.1074/jbc.M112.428458

Abstract

The peripheral dopaminergic system plays a crucial role in blood pressure regulation through its actions on renal hemodynamics and epithelial ion transport. The dopamine D5 receptor (D5R) interacts with sorting nexin 1 (SNX1), a protein involved in receptor retrieval from the trans-Golgi network. In this report, we elucidated the spatial, temporal, and functional significance of this interaction in human renal proximal tubule cells and HEK293 cells stably expressing human D5R and in mice. Silencing of SNX1 expression via RNAi resulted in the failure of D5R to internalize and bind GTP, blunting of the agonist-induced increase in cAMP production and decrease in sodium transport, and up-regulation of angiotensin II receptor expression, of which expression was previously shown to be negatively regulated by D5R. Moreover, siRNA-mediated depletion of renal SNX1 in C57BL/6J and BALB/cJ mice resulted in increased blood pressure and blunted natriuretic response to agonist in salt-loaded BALB/cJ mice. These data demonstrate a crucial role for SNX1 in D5R trafficking and that SNX1 depletion results in D5R dysfunction and thus may represent a novel mechanism for the pathogenesis of essential hypertension. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

APA Citation

Villar, V., Jones, J., Armando, I., Asico, L., Escano, C., Lee, H., Wang, X., Yang, Y., Pascua-Crusan, A., Palmes-Saloma, C., Felder, R., & Jose, P. (2013). Sorting nexin 1 loss results in D₅ dopamine receptor dysfunction in human renal proximal tubule cells and hypertension in mice. Journal of Biological Chemistry, 288 (1). http://dx.doi.org/10.1074/jbc.M112.428458