Regulation of Urea Transport by Adrenal Steroids

如果没有浓缩尿液的能力，地球上的生命将是悲惨的。糖皮质激素是主要的分解代谢激素，可导致蛋白质分解和尿素生成。尿素排泄到尿液中是消除体内多余氮的主要机制。尿素转运体对于解释尿液浓缩时发生的生理过程的理论至关重要。仅在14年前，关于这种转运体的证据在很大程度上是推测性的，但我们提供了实验证据，证明肾脏内髓集管中有促进尿素运输的物质。随后，从肾髓质（UT-A1, UT-A2, UT-A3, UT-A4）、睾丸（UT-A5）和红细胞（UT-B）中克隆了尿素转运蛋白的cDNA同种异构体。最近，我们克隆了大鼠和人类尿素转运蛋白UT-A家族的基因，发现有2个启动子：启动子I位于5'至外显子1，控制UT-A1， UT-A3和UT-A4的转录；启动子II位于内含子12上，控制UT-A2的转录。通过研究5种与尿浓缩能力受损相关的动物模型，我们小组在了解尿素运输的长期调控方面也取得了重大进展。我们的研究得出了一个令人惊讶的结果，在体内条件下，尿浓缩能力和血浆加压素水平降低，促进尿素通透性和UT-A1蛋白丰度增加。我们还发现UT-A1蛋白丰度在体内与糖皮质激素增加相关的条件下降低。

Terrestrial life would be miserable without the ability to concentrate the urine. Glucocorticoids are the primary catabolic hormone that causes protein breakdown and ureagenesis. Urea excretion into the urine is the primary mechanism for eliminating this excess nitrogen from the body. A urea transporter is critically important to the theories proposed to explain the physiologic processes occurring when urine is concentrated. Only 14 years ago, evidence for such a transporter was largely speculative, but we provided experimental evidence that there is facilitated urea transport in the kidney inner medullary collecting duct. Subsequently, cDNA isoforms for facilitated urea transporters were cloned from kidney medulla (UT-A1, UT-A2, UT-A3, UT-A4), testis (UT-A5), and erythrocytes (UT-B). Recently, we cloned the rat and human genes for the UT-A family of urea transporters and showed that there are 2 promoters: promoter I, located 5' to exon 1, that controls transcription of UT-A1, UT-A3, and UT-A4; and promoter II, located in intron 12, that controls transcription of UT-A2. Our group has also made major progress in understanding the long-term regulation of urea transport by studying 5 animal models associated with an impaired urine concentrating ability. Our studies led to the surprising result that facilitated urea permeability and UT-A1 protein abundance are increased during in vivo conditions associated with a reduced urine concentrating ability and plasma vasopressin level. We also found that UT-A1 protein abundance is decreased during in vivo conditions associated with increased glucocorticoids.