Abstract Body: Sorting nexin 19 (SNX19) is a lipid raft-associated protein that contains binding domains for caveolin-1 and flotillin-1 and plays a regulatory role in dopamine D1 receptor (D₁R) trafficking in renal proximal tubule cells (RPTCs). However, its role on D₁R protein expression remains incompletely understood. In human RPTCs, SNX19 colocalized and co-immunoprecipitated with caveolin-1 and flotillin-1, and their interactions were further enhanced by fenoldopam (25 nM, 30 min), a D₁R/D₅R agonist. In mouse RPTCs transfected with Snx19, deletion of the caveolin-1 or flotillin-1 binding sites did not alter D₁R expression. By contrast, targeted knockdown of SNX19 via siRNA in human RPTCs significantly reduced D₁R protein abundance (non-silencing siRNA: 100±5.0%; SNX19 siRNA: 45±6.1%; P<0.05) and blunted the fenoldopam-stimulated cAMP generation (mock siRNA: +147.8±4.5 pmol/mg protein; SNX19 siRNA: +56.3±5.4 pmol/mg protein; P<0.05; n=4). Silencing Snx19 also led to a decrease in D₁R protein levels in mouse kidney homogenates (mock siRNA: 1.0±0.09; Snx19 siRNA: 0.57±0.17; P<0.05; n=5). Consistent with these findings, RPTCs from hypertensive individuals had decreased SNX19 protein expression, relative to normotensive controls (100.0±12.4% vs. 38.7±8.7%; P<0.05; n=4). Furthermore, renal-restricted silencing of Snx19 via renal subcapsular infusion of specific Snx19 siRNA in C57Bl/6J mice decreased D₁R but increased Na⁺/K⁺-ATPase protein and systolic blood pressure (mock siRNA: 101±6 mmHg; Snx19 siRNA: 118±5 mmHg; P<0.05; n=5). Collectively, deficiency of SNX19 decreases D₁R protein in renal proximal tubules and increases systolic blood pressure in mice.