Functional analysis of antidiuretic hormone receptor using V1a knockout mice and invention of new diuretics.
V1a基因敲除小鼠抗利尿激素受体功能分析及新型利尿剂的发明。
基本信息
- 批准号:17590833
- 负责人:
- 金额:$ 2.24万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (C)
- 财政年份:2005
- 资助国家:日本
- 起止时间:2005 至 2006
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Vasopressin V(1a) and V(2) receptors (V(1a)R and V(2)R, respectively) distribute in the collecting duct of the kidney. Although the function of V(2)R mediating the antidiuretic effect of AVP has been investigated in detail, the role of V(la)R in the collecting ducts has not been elucidated. In the present study, we have investigated the role of the V(la)R pathway in V(2)R promoter activity. We cloned the 5'-flanking region of rat V(2)R (rV(2)R) and investigated rV(2)R promoter activity in the LLC-PK(1) cell line transfected to express rat V(la)R (rV(la)R) dominantly (LLC-PK(1)/rV(la)R). AVP induced a transient increase, followed by a sustained decrease, of rV(2)R promoter activity in these cells. This AVP-induced decrease of rV(2)R promoter activity was inhibited by V(1a)R, but not V(2)R, antagonist. PMA mimicked this decrease of rV(2)R promoter activity. On the contrary, cpt-cAMP increased rV(2)1t promoter activity. These PMA-and cpt-cAMP-induced effects were not observed on the deletion segment of the 5'-flanking region lacking CAAT and SP1 sites. In conclusion, 1) expression of the V(2)R is downregulated via the V(la)R pathway in LLC-PK(1)/rV(1a)R cells, and 2) expression of the V(2)R is downregulated by the PMA-induced PKC pathway and upregulated by the cAMP-PKA pathway. These opposite effects of PKC and PKA appear to be regulated by the same promoter region of CAAT and SP1 (published in Am J Physiol.)We also investigated the mechanisms of downregulation of V2 receptor in dehydration. 0ur results indicated that increased production of prostaglandin in renal medulla play a key role for the downregulation. The urine volume of Via knockout mice was smaller than that of wild type, suggestting that Vla knockout mice show a new type of nephrogenic diabetic insipidus.
加压素V(1a)和V(2)受体(分别为V(1a)R和V(2)R)分布于肾脏集合管。虽然V(2)R介导AVP抗利尿作用的功能已被详细研究,但V(1a)R在集合管中的作用尚未阐明。在本研究中,我们研究了V(la)R途径在V(2)R启动子活性中的作用。我们克隆了大鼠V(2)R(rV(2)R)的5 '侧翼区,并在转染以显性表达大鼠V(la)R(rV(la)R)的LLC-PK(1)细胞系(LLC-PK(1)/rV(la)R)中研究了rV(2)R启动子活性。AVP诱导这些细胞中rV(2)R启动子活性的短暂增加,随后持续降低。这种AVP诱导的rV(2)R启动子活性的降低可被V(1a)R拮抗剂所抑制,但不被V(2)R拮抗剂所抑制。PMA模拟了rV(2)R启动子活性的降低。相反,cpt-cAMP增加rV(2)1 t启动子活性。在缺少CAAT和SP1位点的5 ′-侧翼区的缺失片段上未观察到PMA和cpt-cAMP诱导的效应。总之,1)LLC-PK(1)/rV(1a)R细胞中V(2)R的表达通过V(1a)R途径下调,2)V(2)R的表达通过PMA诱导的PKC途径下调,通过cAMP-PKA途径上调。PKC和PKA的这些相反作用似乎由CAAT和SP1的相同启动子区域调节(发表在Am J Physiol.)我们还研究了脱水时V2受体下调的机制。结果表明,肾髓质前列腺素生成增加在下调中起关键作用。Vla基因敲除小鼠尿量明显小于野生型小鼠,提示Vla基因敲除小鼠存在一种新的肾原性尿崩症。
项目成果
期刊论文数量(29)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Inhibition of prostasin-induced ENaC activities by PN-1 and regulation of PN-1 expression TGF-beta aldosterone
PN-1 抑制前列腺素诱导的 ENaC 活性并调节 PN-1 表达 TGF-β 醛固酮
- DOI:
- 发表时间:2006
- 期刊:
- 影响因子:0
- 作者:Wakida N;Nonoguchi H;et al.
- 通讯作者:et al.
Downregulation of vasopressin V2 receptor promoter activity via V1a receptor pathway
- DOI:10.1152/ajprenal.00358.2006
- 发表时间:2007-05-01
- 期刊:
- 影响因子:4.2
- 作者:Izumi, Yuichiro;Nakayama, Yushi;Tomita, Kimio
- 通讯作者:Tomita, Kimio
Mutations in human urate transporter 1 gene in presecretory reabsorption defect type of familial renal hypouricemia
- DOI:10.1210/jc.2004-1111
- 发表时间:2005-04-01
- 期刊:
- 影响因子:5.8
- 作者:Wakida, N;Tuyen, DG;Kitamura, K
- 通讯作者:Kitamura, K
Downregulation of the V2 vasopressin receptor in dehydration: mechanisms and role of renal prostaglandin synthesis
- DOI:10.1152/ajprenal.00154.2006
- 发表时间:2007-04-01
- 期刊:
- 影响因子:4.2
- 作者:Machida, Kenji;Wakamatsu, Shiho;Nonoguchi, Hiroshi
- 通讯作者:Nonoguchi, Hiroshi
Successful treatment of a patient with severe calcific uremic arteriolopathy(calciphylaxis) by etidronate disodium
依替膦酸二钠成功治疗严重钙化性尿毒症性小动脉病(钙化防御)患者
- DOI:
- 发表时间:2006
- 期刊:
- 影响因子:0
- 作者:Shiraishi;N
- 通讯作者:N
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NONOGUCHI Hiroshi其他文献
NONOGUCHI Hiroshi的其他文献
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{{ truncateString('NONOGUCHI Hiroshi', 18)}}的其他基金
The mechanisms of regulation of nuclocytoplasmic transport of mineralocorticoid receptor by vasopressin V1a receptor.
加压素 V1a 受体调节盐皮质激素受体核细胞质转运的机制。
- 批准号:
24591244 - 财政年份:2012
- 资助金额:
$ 2.24万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The role of vasopressin V1a receptor in diabetic nephropathy and the invention of new therapy.
加压素V1a受体在糖尿病肾病中的作用及新疗法的发明。
- 批准号:
21591064 - 财政年份:2009
- 资助金额:
$ 2.24万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The investigation of the role of interaction of two types of antidiuretic hormone receptors for diuresis and the invention of the new therapy for renal edema.
研究两类抗利尿激素受体相互作用对利尿的作用并发明治疗肾水肿的新疗法。
- 批准号:
19590955 - 财政年份:2007
- 资助金额:
$ 2.24万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The investigation of the mechanisms and therapy of the abnormality in antidiuretic hormone action in patients with chronic renal failure
慢性肾功能衰竭患者抗利尿激素作用异常的机制及治疗探讨
- 批准号:
15590852 - 财政年份:2003
- 资助金额:
$ 2.24万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Regulation of diuresis by 2 types of antidiuretic hormone receptor in chronic renal failure and therapeutic investigation of edema
2种抗利尿激素受体对慢性肾功能衰竭利尿的调节及水肿治疗研究
- 批准号:
13671121 - 财政年份:2001
- 资助金额:
$ 2.24万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The study on molecular biological mechanisms and therapy of sodiam and acid disturbance in renal failure
肾衰竭钠酸紊乱的分子生物学机制及治疗研究
- 批准号:
10671000 - 财政年份:1998
- 资助金额:
$ 2.24万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The investigation of molecular biological mechanisms and therapy of refractory renal edema.
难治性肾水肿的分子生物学机制及治疗研究。
- 批准号:
08671291 - 财政年份:1996
- 资助金额:
$ 2.24万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The investigation of the mechanisms and the rapy of renal edema from the acpect of cell porality.
从细胞多孔性角度探讨肾水肿发生机制及治疗方法。
- 批准号:
06671133 - 财政年份:1994
- 资助金额:
$ 2.24万 - 项目类别:
Grant-in-Aid for General Scientific Research (C)