The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion

Renal dopamine D 1 -like receptors (D 1 R and D 5 R) and the gastrin receptor (CCK B R) are involved in the maintenance of sodium homeostasis. The D 1 R has been found to interact synergistically with CCK B R in renal proximal tubule (RPT) cells to promote natriuresis and diuresis. D 5 R, which has a higher affinity for dopamine than D 1 R, has some constitutive activity. Hence, we sought to investigate the interaction between D 5 R and CCK B R in the regulation of renal sodium excretion. In present study, we found D 5 R and CCK B R increase each other’s expression in a concentration- and time-dependent manner in the HK-2 cell, the specificity of which was verified in HEK293 cells heterologously expressing both human D 5 R and CCK B R and in RPT cells from a male normotensive human. The specificity of D 5 R in the D 5 R and CCK B R interaction was verified further using a selective D 5 R antagonist, LE-PM436. Also, D 5 R and CCK B R colocalize and co-immunoprecipitate in BALB/c mouse RPTs and human RPT cells. CCK B R protein expression in plasma membrane-enriched fractions of renal cortex (PMFs) is greater in D 5 R -/- mice than D 5 R +/+ littermates and D 5 R protein expression in PMFs is also greater in CCK B R -/- mice than CCK B R +/+ littermates. High salt diet, relative to normal salt diet, increased the expression of CCK B R and D 5 R proteins in PMFs. Disruption of CCK B R in mice caused hypertension and decreased sodium excretion. The natriuresis in salt-loaded BALB/c mice was decreased by YF476, a CCK B R antagonist and Sch23390, a D 1 R/D 5 R antagonist. Furthermore, the natriuresis caused by gastrin was blocked by Sch23390 while the natriuresis caused by fenoldopam, a D 1 R/D 5 R agonist, was blocked by YF476. Taken together, our findings indicate that CCK B R and D 5 R synergistically interact in the kidney, which may contribute to the maintenance of normal sodium balance following an increase in sodium intake.