The Synergistic Roles of Cholecystokinin B and Dopamine D(5) 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.