title: The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion.
abstract: Renal dopamine D1-like receptors (D1R and D5R) and the gastrin receptor (CCKBR) are involved in the maintenance of sodium homeostasis. The D1R has been found to interact synergistically with CCKBR in renal proximal tubule (RPT) cells to promote natriuresis and diuresis. D5R, which has a higher affinity for dopamine than D1R, has some constitutive activity. Hence, we sought to investigate the interaction between D5R and CCKBR in the regulation of renal sodium excretion. In present study, we found D5R and CCKBR 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 D5R and CCKBR and in RPT cells from a male normotensive human. The specificity of D5R in the D5R and CCKBR interaction was verified further using a selective D5R antagonist, LE-PM436. Also, D5R and CCKBR colocalize and co-immunoprecipitate in BALB/c mouse RPTs and human RPT cells. CCKBR protein expression in plasma membrane-enriched fractions of renal cortex (PMFs) is greater in D5R-/- mice than D5R+/+ littermates and D5R protein expression in PMFs is also greater in CCKBR-/- mice than CCKBR+/+ littermates. High salt diet, relative to normal salt diet, increased the expression of CCKBR and D5R proteins in PMFs. Disruption of CCKBR in mice caused hypertension and decreased sodium excretion. The natriuresis in salt-loaded BALB/c mice was decreased by YF476, a CCKBR antagonist and Sch23390, a D1R/D5R antagonist. Furthermore, the natriuresis caused by gastrin was blocked by Sch23390 while the natriuresis caused by fenoldopam, a D1R/D5R agonist, was blocked by YF476. Taken together, our findings indicate that CCKBR and D5R synergistically interact in the kidney, which may contribute to the maintenance of normal sodium balance following an increase in sodium intake.
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China.
authors.forename: Zihao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors.forename: Robin A
authors.initials: RA
authors.lastname: Felder
authors.affiliation: Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors.forename: John J
authors.initials: JJ
authors.lastname: Gildea
authors.affiliation: Division of Nephrology, Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Qin
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China.|CollaborativeInnovation Center for Cardiovascular Disorders, Beijing, P. R. China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000737:chemistry; D001794:Blood Pressure; D002766:Cholecystokinin / Q000378:metabolism; D005260:Female; D018818:Fenoldopam / Q000737:chemistry; D005755:Gastrins / Q000737:chemistry; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009318:Natriuresis; D043887:Receptor, Cholecystokinin B / Q000378:metabolism*; D050641:Receptors, Dopamine D5 / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*
chemical_list: D001552:Benzazepines; D005755:Gastrins; D043887:Receptor, Cholecystokinin B; C534628:SCH 23390; D050641:Receptors, Dopamine D5; D002766:Cholecystokinin; D012964:Sodium; D018818:Fenoldopam