Urinary concentrating function in mice lacking EP3 receptors for prostaglandin E2
Urinary concentrating function in mice lacking EP3 receptors for prostaglandin E2
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DOI：
10.1152/ajprenal.1998.275.6.f955
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发表时间：
1998-12-01
影响因子：
4.2
通讯作者：
Coffman, TM
中科院分区：
文献类型：
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作者：
Fleming, EF;Athirakul, K;Coffman, TM
前列腺素（PG）E-2的作用由四种不同类型的PGE（2）E-前列腺素（EP）受体（EP 1至EP 4）介导。然而，个别EP受体亚型的体内功能尚未被描述。为了研究这些亚型之一EP 3受体的功能，我们通过基因靶向产生了EP 3缺陷（-/-）小鼠。EP 3-/-动物以预期数量存活，繁殖，并且其主要器官系统无明显异常。由于EP 3受体在肾髓质和皮质集合管中高水平表达，并且由于先前的研究表明EP 3受体可能拮抗血管加压素在远端肾单位中的作用，因此我们检查了EP 3-/-小鼠的尿浓缩功能。基础尿渗透压（U-Osm）在EP 3-/-和野生型（EP 3 +/+）小鼠组中相似。然而，吲哚美辛抑制内源性PGE（2）产生后，EP 3 +/+小鼠的U-Osm显著增加，而EP 3-/-小鼠的U-Osm则没有增加。尽管对前列腺素产生的急性抑制不敏感，EP 3-/-小鼠仍能正常浓缩和稀释尿液，以响应一系列生理刺激。这表明PGE（2）通过EP 3受体调节肾脏中的尿浓缩机制，但这些作用对于尿渗透压的正常调节不是必需的。
The actions of prostaglandin (PG) E-2 are mediated by four distinct classes of PGE(2) E-prostanoid (EP) receptors (EP1 through EP4). However, the in vivo functions of the individual EP receptor subtypes have not been delineated. To study the functions of one of these subtypes, the EP3 receptor, we generated EP3-deficient (-/-) mice by gene targeting. EP3 -/- animals survived in expected numbers, reproduced, and had no obvious abnormalities in their major organ systems. Because the EP3 receptor is expressed at high levels in the renal medulla and cortical collecting duct, and because previous studies have suggested that the EP3 receptor might antagonize the effects of vasopressin in the distal nephron, we examined urinary concentrating functions in EP3 -/- mice. Basal urine osmolality (U-Osm) was similar in groups of EP3 -/- and wild-type (EP3 +/+) mice. However after inhibition of endogenous PGE(2) production by indomethacin, U-Osm increased significantly in EP3 +/+ but not in EP3 -/- mice. Despite this insensitivity to acute inhibition of prostanoid production, EP3 -/- mice concentrated and diluted their urine normally in response to a series of physiological stimuli. This suggests that PGE(2) acts through the EP3 receptor to modulate urinary concentrating mechanisms in the kidney, but these effects are not essential for normal regulation of urinary osmolality.