Department of Medicine, Division of Nephrology, Duke University Medical Center, MSRBII Room 2018, 106 Research Drive, Durham, NC 27710, USA.
J Am Soc Nephrol. 2011 Dec;22(12):2237-46. doi: 10.1681/ASN.2010101095. Epub 2011 Nov 3.
Mice lacking AT(1) angiotensin receptors have an impaired capacity to concentrate the urine, but the underlying mechanism is unknown. To determine whether direct actions of AT(1) receptors in epithelial cells of the collecting duct regulate water reabsorption, we used Cre-Loxp technology to specifically eliminate AT(1A) receptors from the collecting duct in mice (CD-KOs). Although levels of AT(1A) receptor mRNA in the inner medulla of CD-KO mice were significantly reduced, their kidneys appeared structurally normal. Under basal conditions, plasma and urine osmolalities and urine volumes were similar between CD-KO mice and controls. The increase in urine osmolality in response to water deprivation or vasopressin administration, however, was consistently attenuated in CD-KO mice. Similarly, levels of aquaporin-2 protein in inner and outer medulla after water deprivation were significantly lower in CD-KO mice compared with controls, despite its normal localization to the apical membrane. In summary, these results demonstrate that AT(1A) receptors in epithelial cells of the collecting duct directly modulate aquaporin-2 levels and contribute to the concentration of urine.
缺乏 AT(1)血管紧张素受体的小鼠浓缩尿液的能力受损，但潜在机制尚不清楚。为了确定 AT(1)受体在集合管上皮细胞中的直接作用是否调节水的重吸收，我们使用 Cre-Loxp 技术特异性地从收集管中消除了小鼠（CD-KO）中的 AT(1A)受体。尽管 CD-KO 小鼠的内髓质 AT(1A)受体 mRNA 水平显著降低，但它们的肾脏外观结构正常。在基础条件下，CD-KO 小鼠和对照组的血浆和尿液渗透压以及尿量相似。然而，对水剥夺或血管加压素给药的尿液渗透压升高的反应，在 CD-KO 小鼠中始终减弱。同样，尽管水剥夺后 CD-KO 小鼠的 aquaporin-2 蛋白水平正常定位在顶膜上，但与对照组相比，其在内外髓质中的水平明显降低。总之，这些结果表明，集合管上皮细胞中的 AT(1A)受体直接调节 aquaporin-2 水平并有助于尿液浓缩。
