Sorting Nexin 1 Loss Results in D5 Dopamine Receptor Dysfunction in Human Renal Proximal Tubule Cells and Hypertension in Mice
Open accessAbstract
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 (D(5)R) 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 D(5)R and in mice. Silencing of SNX1 expression via RNAi resulted in the failure of D(5)R 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 D(5)R. 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 D(5)R trafficking and that SNX1 depletion results in D(5)R dysfunction and thus may represent a novel mechanism for the pathogenesis of essential hypertension.
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SNX exhibits its function by regulating expression and function of GPCRs such as RTKs and dopamine receptors for maintenance of blood pressure.
“Accumulating reports revealed that SNX exhibits its function by regulating expression and function of G protein-coupled receptors (GPCRs) such as receptor tyrosine kinases (RTKs) and dopamine receptors for the maintenance of blood pressure [129,130].”
From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [130]
Cites
Haft, C. R., de la Luz Sierra, M., Barr, V. A., Haft, D. H., & Taylor, S. I. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.12.7278 · Cited by 244 · see citing works
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Insights of Endocytosis Signaling in Health and Disease
Pathak, C., Vaidya, F. U., Waghela, B. N., Jaiswara, P. K., Gupta, V. K., Kumar, A., Rajendran, B. K., & Ranjan, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032971 · Cited by 59 · see citing works
- Authors
- Villar, V. A. M., Jones, J. E., Armando, I., Asico, L. D., Escano, C. S., Lee, H., Wang, X., Yang, Y., Pascua-Crusan, A. M., Palmes-Saloma, C. P., Felder, R. A., & Jose, P. A.
- Affiliations
- Children's National (US)
- University of the Philippines Diliman (PH)
- University of Virginia (US)
- Corresponding author
- Villar, Van Anthony M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 288
- Issue
- 1
- Pages
- 152-163
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3537009
- OpenAlex
- W2011459847
- Cited by
- 33
- References
- 1
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 6 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 1 · 2015: 3 · 2014: 2 · 2013: 1
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1s10rr015768-01)
- National Heart, Lung, and Blood Institute (HL-092196, P01HL074940, HL23081, HL‐68686, R37HL023081, HL074940, P01HL068686, R01HL023081, R01HL092196)
- National Cancer Institute (2P30-CA-51008, P30CA051008)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK039308, DK-39308, R01DK090918)
- National Center for Research Resources (KL2RR031987, 1 S10 RR 15768-01, UL1RR031988)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- SNX1, dopamine D5 receptor, receptor trafficking, proximal tubular epithelial cells, essential hypertension, angiotensin II receptor, sodium transport, cAMP signaling, receptor internalization, trans-Golgi network, sodium excretion, blood pressure regulation
- MeSH terms
- Cyclic AMP, Animals, Cell Membrane, Gene Expression Regulation, Guanosine Triphosphate, Humans, Hypertension, Kidney Tubules, Proximal, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Models, Biological, Mice, Knockout, Gene Silencing, Fluorescence Resonance Energy Transfer, RNA Interference, Receptors, Dopamine D5, Mice, HEK293 Cells, Sorting Nexins
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