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Increased AT₁ receptor expression mediates vasoconstriction leading to hypertension in Snx1^-/- mice.

ABSTRACT: Angiotensin II type 1 receptor (AT₁R) is a vital therapeutic target for hypertension. Sorting nexin 1 (SNX1) participates in the sorting and trafficking of the renal dopamine D₅ receptor, while angiotensin and dopamine are counterregulatory factors in the regulation of blood pressure. The effect of SNX1 on AT₁R is not known. We hypothesized that SNX1, through arterial AT₁R sorting and trafficking, is involved in blood pressure regulation. CRISPR/Cas9 system-generated SNX1^-/- mice showed dramatic elevations in blood pressure compared to their wild-type littermates. The angiotensin II-mediated contractile reactivity of the mesenteric arteries and AT₁R expression in the aortas were also increased. Moreover, immunofluorescence and immunoprecipitation analyses revealed that SNX1 and AT₁R were colocalized and interacted in the aortas of wild-type mice. In vitro studies revealed that AT₁R protein levels and downstream calcium signaling were upregulated in A10 cells treated with SNX1 siRNA. This may have resulted from decreased AT₁R protein degradation since the AT₁R mRNA levels showed no changes. AT₁R protein was less degraded when SNX1 was downregulated, as reflected by a cycloheximide chase assay. Furthermore, proteasomal rather than lysosomal inhibition increased AT₁R protein content, and this effect was accompanied by decayed binding of ubiquitin and AT₁R after SNX1 knockdown. Confocal microscopy revealed that AT₁R colocalized with PSMD6, a proteasomal marker, and the colocalization was reduced after SNX1 knockdown. These findings suggest that SNX1 sorts AT₁R for proteasomal degradation and that SNX1 impairment increases arterial AT₁R expression, leading to increased vasoconstriction and blood pressure.

SUBMITTER: Liu C

PROVIDER: S-EPMC8590203 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Intracellular Ca2+ is critical for regulating airway smooth muscle (ASM) tension. A rapid rise in the intracellular Ca2+ concentration ([Ca2+]i) of ASM cells is crucial for modulating the intensity and length of the ASM contraction. Because this rapid increase in [Ca2+]i largely depends on the balance between Ca2+ released from intracellular Ca2+ stores and extracellular Ca2+ entry, exploring the mechanisms mediating Ca2+ transport is critical for understanding ASM contractility and the pathogenesis of bronchial contraction disorders. Transient receptor potential vanilloid 4 (TRPV4) is a highly Ca2+-permeable non-selective cation channel that mediates Ca2+ influx to increase [Ca2+]i, which then directly or indirectly regulates the contraction and relaxation of ASM. The [Ca2+]i returns to basal levels through several uptake and extrusion pumps, such as the sarco(endo)plasmic reticulum Ca2+ ATPase and inositol 1,4,5-trisphosphate receptors (IP3Rs), the plasmalemmal Ca2+ ATPase, and the plasma membrane Na+/Ca2+ exchanger (NCX). Thus, to further understand ASM tension regulation in normal and diseased tissue, the present study examined whether an interaction exists among TRPV4, IP3Rs, and NCX. The TRPV4-specific and potent agonist GSK1016790A increased [Ca2+]i in mouse ASM cells, an effect that was completely blocked by the TRPV4-specific antagonist HC067047. However, GSK1016790A induced relaxation in mouse tracheal rings precontracted with carbachol in vitro. To determine the mechanism underlying this TRPV4-induced relaxation of ASM, we blocked specific downstream molecules. We found that the GSK1016790A-induced relaxation was abolished by the NCX inhibitors KB-R7943 and LiCl but not by specific inhibitors of the Ca2+-activated large-, intermediate-, or small-conductance K+ channels (BKCa, IK, and SK3, respectively). The results of co-immunoprecipitation (co-IP) assays showed an interaction of TRPV4 and IP3R1 with NCXs. Taken together, these findings support a physical and functional interaction of TRPV4 and IP3R1 with NCXs as a novel TRPV4-mediated Ca2+ signaling mechanism and suggest a potential target for regulation of ASM tension and treatment of respiratory diseases, especially tracheal spasm.

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Increased AT₁ receptor expression mediates vasoconstriction leading to hypertension in Snx1^-/- mice.

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