Intrarenal Dopaminergic System Is Dysregulated in SS-Resp18(mutant) Rats

The genetic and molecular basis of developing high blood pressure and renal disease are not well known. Resp18(mutant) Dahl salt-sensitive (SS-Resp18(mutant)) rats fed a 2% NaCl diet for six weeks have high blood pressure, increased renal fibrosis, and decreased mean survival time. Impairment of the dopaminergic system also leads to hypertension that involves renal and non-renal mechanisms. Deletion of any of the five dopamine receptors may lead to salt-sensitive hypertension. Therefore, we investigated the interaction between Resp18 and renal dopamine in SS-Resp18(mutant) and Dahl salt-sensitive (SS) rats. We found that SS-Resp18(mutant) rats had vascular dysfunction, as evidenced by a decrease in vasorelaxation in response to sodium nitroprusside. The pressure–natriuresis curve in SS-Resp18(mutant) rats was shifted down and to the right of SS rats. SS-Resp18(mutant) rats had decreased glomerular filtration rate and dopamine receptor subtypes, D1R and D5R. Renal dopamine levels were decreased, but urinary dopamine levels were increased, which may be the consequence of increased renal dopamine production, followed by secretion into the tubular lumen. The increased renal dopamine production in SS-Resp18(mutant) rats in vivo was substantiated by the increased dopamine production in renal proximal tubule cells treated with L-DOPA. Overall, our study provides evidence that targeted disruption of the Resp18 locus in the SS rat dysregulates the renal dopaminergic system.