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）：肾原性糖尿病（NDI）是一种疾病，其特征是从肾脏无法对加压素反应的肾脏产生大量稀释的尿液。 NDI可以是先天性或获得的。先天性NDI是由90％家族中2型加压素受体（V2R）突变（其中已知突变）和其他10％的AQP2的突变引起的。获得NDI的最常见原因是锂治疗，这种药物会干扰cAMP信号。在患有V2R突变或服用锂的患者中，AQP2或UT-A1蛋白质中都没有突变，这表明如果可以磷酸化这些蛋白质并增加与血管封发蛋白或CAMP无关的顶膜积累，那么它可能会治疗或至少能够治疗NDI的严重程度。因此，我们寻找一种可以独立于加压素磷酸化的AQP2和UT-A1的激酶。腺苷一磷酸激酶（AMPK）是一种能量激酶，可以通过渗透应激和缺氧刺激。 AMPK从未在内部延髓中进行研究，该内部通常是高渗和低氧。我们的初步数据表明，AMPK在体外和天然大鼠内髓质收集导管中磷酸化AQP2和UT-A1。我们还拥有初步数据，表明二甲双胍会增加缺乏先天性NDI小鼠模型V2R的小鼠的尿液渗透压。在此应用中，我们将检验以下假设：与加压素无关的AMPK通过增加AQP2和UT-A1磷酸化，顶端质膜积累和功能来提高尿液浓缩能力。特定的目标1将测试AQP2和UT-A1是否是AMPK磷酸化的底物。特定的目标2将测试AMPK对AQP2和UT-A1的磷酸化是否会增加这两种蛋白质的顶膜积累。特定的目标3将测试AMPK的激活是否会增加尿素和水的渗透率，以及NDI动物模型中的尿液浓缩能力。如果我们的假设是正确，然后，由于V2R突变，AMPK激活剂将成为先天性NDI的新型治疗选择，并且由于干扰了CAMP，因此对于获得的NDI形式。

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）

Functional characterization of the central hydrophilic linker region of the urea transporter UT-A1: cAMP activation and snapin binding.

尿素转运蛋白 UT-A1 中央亲水连接区的功能表征：cAMP 激活和管理单元结合。

DOI：
10.1152/ajpcell.00497.2009
发表时间：
2010
期刊：
American journal of physiology. Cell physiology
影响因子：
0
作者：
Mistry,AbinashC;Mallick,Rickta;Klein,JanetD;Sands,JeffM;Fröhlich,Otto
通讯作者：
Fröhlich,Otto

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。