Regulation of Urea Transport in Diabetic Rat Kidney

糖尿病大鼠肾脏尿素转运的调控

• 批准号: 7191746
• 负责人: JANET D KLEIN
• 金额: $ 28.72万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7191746
• 关键词: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Carrier Proteins; Complex; Condition; Data; Diabetes Mellitus; Diabetic Ketoacidosis; Diuresis; Duct (organ) structure; Event; Glucocorticoids; Glucose; Goals; Homeostasis; Hormonal; Hormones; Human; Hypovolemic Shock; Immunohistochemistry; Insulin-Dependent Diabetes Mellitus; Ion Channel; KCNJ1 gene; Kidney; Knockout Mice; Link; Mediating; Metabolic; Modeling; Molecular; Paper; Patients; Permeability; Phosphorylation; Plasma; Polyuria; Principal Investigator; Protein Kinase C; Protein Kinase C Inhibitor; Proteins; Publishing; Rattus; Regulation; Renin-Angiotensin System; Role; Signaling Protein; Sodium; Streptozocin; Streptozocin Diabetes; Testing; Time; Urea; Vasopressins; Water; activator 1 protein; aquaporin 3; aquaporin-2; base; day; diabetes mellitus therapy; diabetic; diabetic rat; insight; novel; prevent; programs; protein expression; receptor; response; sodium-potassium chloride cotransporter 2 protein; solute; urea transporter; water channel

DESCRIPTION (provided by applicant): The polyuria that occurs in diabetic patients is generally ascribed to an osmotic diuresis. However, we believe that the mechanisms are more complex. The major goal of this proposal is to identify the cellular and molecular mechanisms that contribute to changes in water and solute homeostasis that occur in uncontrolled diabetes. Several metabolic and hormonal abnormalities present in diabetes could contribute to a loss of water and solute or compensatory mechanisms to limit these losses. We plan to evaluate the role of vasopressin and glucocorticoids in regulating medullary transport proteins in diabetic rats since these animals (and humans) have elevated levels of both hormones. We also plan to evaluate the role of angiotensin II since its inhibition is a mainstay of current therapy for diabetes. Identifying these mechanisms could provide novel insights into the compensatory mechanisms that must occur in the kidney that permit patients with uncontrolled type I diabetes to limit the loss of water and solute, thereby limiting volume depletion. HYPOTHESIS - A compensatory response by the kidney to uncontrolled diabetes is to alter the expression and function of medullary transport proteins to limit the loss of water and solute. Specific Aim 1: we will test whether expression of urea transporters, aquaporins, and ion channels or transporters are altered in rats with uncontrolled diabetes. Rationale: we have preliminary data showing that 10-20 days of diabetes results in an increase in UT-A1, AQP2, and NKCC2/BSC1 protein abundances. Specific Aim 2: we will determine the requirement for vasopressin and/or glucocorticoids in the regulation of urea, water, and sodium transporter proteins in rats with diabetes. Rationale: we have preliminary data showing that UT-A1 and AQP2 protein abundances do not increase in the absence of glucocorticoids or vasopressin. Specific Aim 3: we will determine whether blockade of the renin-angiotensin system alters the regulation of urea, water, and sodium transporter proteins in rats with diabetes. Rationale: blockade of the renin-angiotensin system may prevent compensatory changes and worsen water and solute loss. Specific Aim 4: we will test whether rapid regulation of urea transporter phosphorylation or function is altered by vasopressin and/or angiotensin II in inner medullary collecting ducts (IMCDs) from rats with diabetes. Rationale: angiotensin II increases phosphorylation of UT-A1 in rat IMCDs through PKC. We have preliminary data showing that PKC inhibition reduces UT-A1 phosphorylation in inner medulla from diabetic rats.

描述（由申请人提供）：糖尿病患者发生的多尿通常归因于渗透性利尿。然而，我们认为其机制更为复杂。该提案的主要目标是确定导致不受控制的糖尿病中发生的水和溶质稳态变化的细胞和分子机制。糖尿病中存在的几种代谢和激素异常可能导致水分和溶质的损失或限制这些损失的补偿机制。我们计划评估加压素和糖皮质激素在调节糖尿病大鼠髓质转运蛋白中的作用，因为这些动物（和人类）的两种激素水平升高。我们还计划评估血管紧张素 II 的作用，因为它的抑制是当前糖尿病治疗的支柱。识别这些机制可以为肾脏中必须发生的补偿机制提供新的见解，从而允许未受控制的 I 型糖尿病患者限制水和溶质的损失，从而限制容量消耗。假设 - 肾脏对不受控制的糖尿病的代偿反应是改变髓质转运蛋白的表达和功能，以限制水分和溶质的损失。 具体目标 1：我们将测试糖尿病不受控制的大鼠中尿素转运蛋白、水通道蛋白和离子通道或转运蛋白的表达是否发生改变。理由：我们的初步数据显示，糖尿病 10-20 天会导致 UT-A1、AQP2 和 NKCC2/BSC1 蛋白丰度增加。 具体目标 2：我们将确定糖尿病大鼠尿素、水和钠转运蛋白调节中加压素和/或糖皮质激素的需求。理由：我们的初步数据显示，在没有糖皮质激素或加压素的情况下，UT-A1 和 AQP2 蛋白丰度不会增加。 具体目标 3：我们将确定肾素-血管紧张素系统的阻断是否会改变糖尿病大鼠中尿素、水和钠转运蛋白的调节。理由：阻断肾素-血管紧张素系统可能会阻止代偿性变化并加剧水和溶质的损失。具体目标 4：我们将测试糖尿病大鼠内髓集合管 (IMCD) 中加压素和/或血管紧张素 II 是否改变尿素转运蛋白磷酸化或功能的快速调节。原理：血管紧张素 II 通过 PKC 增加大鼠 IMCD 中 UT-A1 的磷酸化。我们的初步数据表明，PKC 抑制可降低糖尿病大鼠髓质内 UT-A1 的磷酸化。