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Regulation of Renal Inner Medullary Function

肾内髓功能的调节

基本信息

批准号：
9447665
负责人：
JEFF M. SANDS
金额：
$ 6.11万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9447665
关键词：
Adenosine Monophosphate Animal Model Apical Cell membrane Chronic Cultured Cells Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Defect Disease Duct (organ) structure Family Funding Future Hypoxia In Vitro Kidney Kidney Concentrating Ability Knockout Mice Lead Lithium Mediating Metformin Mus Mutate Mutation Osmolalities Patients Permeability Pharmaceutical Preparations Phosphorylation Phosphotransferases Production Proteins Rattus Regulation Retrieval Severities Signal Pathway Signal Transduction Stress Suspensions Testing Therapeutic Urea Urine Vasopressin Receptor Vasopressins Water activator 1 protein apical membrane aquaporin-2 in vitro Assay mouse model novel therapeutic intervention novel therapeutics prevent public health relevance symporter translational study urea transporter vasopressin resistant diabetes insipidus water channel

项目摘要

DESCRIPTION (provided by applicant): Nephrogenic diabetes insipidus (NDI) is a disease characterized by the production of very large quantities of dilute urine from an inability of the kidney to respond to vasopressin. NDI can be either congenital or acquired. Congenital NDI results from mutations in the type 2 vasopressin receptor (V2R) in 90% of families (in which the mutation is known) and in AQP2 in the other 10%. The most common cause of acquired NDI is lithium treatment, a medication that interferes with cAMP signaling. In patients with V2R mutations or taking lithium, there are no mutations in either the AQP2 or UT-A1 proteins, suggesting that if it is possible to phosphorylate these proteins and increase their apical membrane accumulation independent of vasopressin or cAMP, then one may be able to treat, or at least lessen the severity of, the NDI. Therefore, we looked for a kinase that could phosphorylate both AQP2 and UT-A1 independent of vasopressin. Adenosine monophosphate kinase (AMPK) is an energy-sensing kinase that can be stimulated by osmotic stress and hypoxia. AMPK has never been studied in inner medulla, which is normally hypertonic and hypoxic. We have preliminary data showing that AMPK phosphorylates AQP2 and UT-A1, both in vitro and in native rat inner medullary collecting ducts. We also have preliminary data showing that metformin increases urine osmolality in mice lacking a V2R, a mouse model of congenital NDI. In this application, we will test the hypothesis that AMPK, independent of vasopressin, increases urine concentrating ability through increases in AQP2 and UT-A1 phosphorylation, apical plasma membrane accumulation, and function. Specific Aim 1 will test whether AQP2 and UT-A1 are substrates for phosphorylation by AMPK. Specific Aim 2 will test whether phosphorylation of AQP2 and UT-A1 by AMPK increases the apical membrane accumulation of these two proteins. Specific Aim 3 will test whether activation of AMPK increases urea and water permeabilities, and urine concentrating ability in animal models of NDI. If our hypothesis is correct, then AMPK activators would be a novel therapeutic option for congenital NDI due to V2R mutations, and for acquired forms of NDI due to interference with cAMP.

描述（由申请人提供）：肾源性尿崩症（NDI）是一种疾病，其特征是由于肾脏无法对加压素产生反应而产生大量稀尿。NDI可以是先天性的，也可以是后天的。先天性NDI是由90%的家族中的2型加压素受体（V2 R）突变和另外10%的AQP 2突变引起的。获得性NDI最常见的原因是锂治疗，这是一种干扰cAMP信号传导的药物。在V2 R突变或服用锂的患者中，AQP 2或UT-A1蛋白均没有突变，这表明如果有可能磷酸化这些蛋白并增加其顶膜积聚，而不依赖于加压素或cAMP，则可能能够治疗或至少减轻NDI的严重程度。因此，我们寻找一种能够独立于加压素磷酸化AQP 2和UT-A1的激酶。腺苷一磷酸激酶（AMPK）是一种能量敏感激酶，可被渗透胁迫和缺氧刺激。在正常情况下高渗缺氧的延髓内部，AMPK从未被研究过。我们有初步的数据表明，AMPK磷酸化AQP 2和UT-A1，在体外和本地大鼠内髓集合管。我们也有初步数据显示二甲双胍增加缺乏V2 R的小鼠（一种先天性NDI小鼠模型）的尿渗透压。在本申请中，我们将检验AMPK独立于加压素通过增加AQP 2和UT-A1磷酸化、顶端质膜蓄积和功能来增加尿液浓缩能力的假设。具体目标1将测试AQP 2和UT-A1是否是AMPK磷酸化的底物。特异性目标2将测试AMPK对AQP 2和UT-A1的磷酸化是否会增加这两种蛋白质的顶膜积累。具体目标3将测试AMPK的活化是否增加NDI动物模型中的尿素和水渗透性以及尿浓缩能力。如果我们假设正确，那么AMPK激活剂将是由于V2 R突变引起的先天性NDI和由于干扰cAMP引起的获得性NDI的新的治疗选择。

项目成果

期刊论文数量（119）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Urea Transporter B and MicroRNA-200c Differ in Kidney Outer Versus Inner Medulla Following Dehydration.

DOI：
10.1016/j.amjms.2016.06.003
发表时间：
2016-09
期刊：
AMERICAN JOURNAL OF THE MEDICAL SCIENCES
影响因子：
3.1
作者：
Wang, Juan;Wang, Xiaonan H.;Wang, Haidong;Chen, Ling;Klein, Janet D.;Sands, Jeff M.
通讯作者：
Sands, Jeff M.

Urinary concentration and dilution in the aging kidney.

肾脏肾脏的尿液浓度和稀释。

DOI：
10.1016/j.semnephrol.2009.07.004
发表时间：
2009-11
期刊：
SEMINARS IN NEPHROLOGY
影响因子：
3.3
作者：
Sands, Jeff M.
通讯作者：
Sands, Jeff M.

Vasopressin rapidly increases phosphorylation of UT-A1 urea transporter in rat IMCDs through PKA.

DOI：
10.1152/ajprenal.0054.2001
发表时间：
2002
期刊：
American journal of physiology. Renal physiology
影响因子：
0
作者：
Chi Zhang;J. Sands;J. Klein
通讯作者：
Chi Zhang;J. Sands;J. Klein

Impaired urine concentration and absence of tissue ACE: involvement of medullary transport proteins.

尿液浓度受损和组织 ACE 缺失：髓质转运蛋白参与。

DOI：
10.1152/ajprenal.00326.2001
发表时间：
2002
期刊：
American journal of physiology. Renal physiology
影响因子：
0
作者：
Klein,JanetD;LeQuach,D;Cole,JustinM;Disher,Kevin;Mongiu,AnneK;Wang,Xiaodan;Bernstein,KennethE;Sands,JeffM
通讯作者：
Sands,JeffM

Urine-concentrating ability in the aging kidney.

老化肾脏的尿液浓缩能力。