The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion.
The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion.
复制标题
胆囊收缩素B和多巴胺D-5受体对肾钠排泄调节的协同作用
DOI：
10.1371/journal.pone.0146641
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Jiang X;Chen W;Liu X;Wang Z;Liu Y;Felder RA;Gildea JJ;Jose PA;Qin C;Yang Z
肾脏多巴胺D1样受体（D1 R和D5 R）和胃泌素受体（CCKBR）参与钠稳态的维持。已发现D1 R与肾近曲小管（RPT）细胞中的CCK BR协同相互作用，以促进钠尿和利尿。D5 R对多巴胺的亲和力高于D1 R，具有一定的组成活性。因此，我们试图研究D5 R和CCKBR在调节肾钠排泄方面的相互作用。在本研究中，我们发现D5 R和CCKBR在HK-2细胞中以浓度和时间依赖性的方式增加彼此的表达，其特异性在异源表达人D5 R和CCKBR的HEK 293细胞和来自男性正常血压人的RPT细胞中得到验证。D5 R和CCKBR相互作用中D5 R的特异性使用选择性D5 R拮抗剂LE-PM 436进一步验证。此外，D5 R和CCKBR在BALB/c小鼠RPT和人RPT细胞中共定位和共免疫沉淀。D5 R-/-小鼠肾皮质（PMF）质膜富集组分中的CCKBR蛋白表达高于D5 R +/+同窝小鼠，CCKBR-/-小鼠PMF中的D5 R蛋白表达也高于CCKBR+/+同窝小鼠。高盐饮食使PMFs中CCKBR和D5 R蛋白表达增加。破坏小鼠的CCKBR可引起高血压和钠排泄减少。CCKBR拮抗剂YF 476和D1 R/D5 R拮抗剂Sch 23390可减少盐负荷小鼠的尿钠排泄。此外，Sch 23390可阻断胃泌素引起的尿钠排泄，而YF 476可阻断D1 R/D5 R激动剂非诺多泮引起的尿钠排泄。综上所述，我们的研究结果表明，CCKBR和D5 R协同相互作用，在肾脏，这可能有助于维持正常的钠平衡后，增加钠摄入量。
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.