Regulation of V2R transcription by hypertonicity and V1aR-V2R signal interaction
Regulation of V2R transcription by hypertonicity and V1aR-V2R signal interaction
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DOI：
10.1152/ajprenal.00119.2008
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发表时间：
2008-10-01
影响因子：
4.2
通讯作者：
Tomita, Kimio
中科院分区：
文献类型：
--
作者：
Izumi, Yuichiro;Nakayama, Yushi;Tomita, Kimio
精氨酸加压素（AVP）和肾髓质的高渗性在尿浓缩机制中起主要作用。以前，我们表明，大鼠加压素V2受体（rV 2 R）启动子活性增加加压素V2 R刺激和减少加压素V1 a受体（V1 aR）刺激LLC-PK 1细胞系稳定表达大鼠V1 aR（LLC-PK 1/rV 1aR）。在本研究中，我们研究了高渗对LLC-PK 1/rV 1aR细胞中rV 2 R启动子活性的影响以及V1 aR刺激对rV 2 R启动子活性的抑制。rV 2 R启动子活性在NaCl或甘露醇诱导的高渗中增加。rV 2 R启动子区的高渗反应位点被限制在10 bp，包括Sp1基序。JNK抑制剂（SP 600125）和PKA抑制剂（H89）可显著抑制高渗引起的V2 R启动子活性的增加。与此相反，rV 2 R启动子活性显着抑制V1 aR刺激在高渗条件下，而不是在等渗条件下。在高渗条件下，AVP刺激的细胞内Ca 2+浓度增加，表明高渗对V1 aR的功能性激活。总之，1）V2 R启动子活性通过JNK和PKA途径通过高渗增加，2）V1 aR-Ca 2+途径对V2 R表达的抑制通过高渗增强，和3）高渗增强V1 aR-Ca 2+途径。在脱水状态下，可能需要V2 R和V1 aR的反作用来维持最小尿量。
Arginine vasopressin (AVP) and hypertonicity in the renal medulla play a major role in the urine concentration mechanism. Previously, we showed that rat vasopressin V2 receptor (rV2R) promoter activity was increased by vasopressin V2R stimulation and decreased by vasopressin V1a receptor (V1aR) stimulation in a LLC-PK1 cell line stably expressing rat V1aR (LLC-PK1/rV1aR). In the present study, we investigated the effects of hypertonicity on the rV2R promoter activity and on the suppression of rV2R promoter activity by V1aR stimulation in LLC-PK1/rV1aR cells. rV2R promoter activity was increased in NaCl- or mannitol-induced hypertonicity. The hypertonicity-responsive site in the rV2R promoter region was limited to 10 bp, including the Sp1 motif. The increase of V2R promoter activity by hypertonicity was significantly inhibited by a JNK inhibitor (SP600125) and PKA inhibitor (H89). In contrast, rV2R promoter activity was remarkably suppressed by V1aR stimulation in the hypertonic condition rather than in the isotonic condition. The AVP-stimulated intracellular Ca2+ concentration was increased in the hypertonic condition, suggesting the functional activation of V1aR by hypertonicity. In conclusion, 1) V2R promoter activity is increased by hypertonicity via the JNK and PKA pathways, 2) suppression of V2R expression by the V1aR-Ca2+ pathway is enhanced by hypertonicity, and 3) hypertonicity enhances the V1aR-Ca2+ pathway. The counteractivity of V2R and V1aR could be required to maintain minimum urine volume in the dehydrated state.