Renal Sodium Transport in the Obese Zucker Rat

肥胖 Zucker 大鼠的肾钠转运

基本信息

批准号：
7340799
负责人：
Carolyn Mary Ecelbarger
金额：
$ 2.33万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-06-01 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7340799
关键词：
Acute Age Agonist Aldosterone Angiotensin II Angiotensin-Converting Enzyme Inhibitors Angiotensins Autoradiography Binding Blood Pressure Canrenone Carrier Proteins Collagen Type IV Data Diabetes Mellitus Diet Disease model Distal Down-Regulation Enalapril Endocrine Enzymes Epithelial Equilibrium Etiology Fibronectins Glucocorticoids Goals Homeostasis Hormones Hyperinsulinism Hypertension Hypertrophy In Situ In Situ Hybridization In Vitro Infusion procedures Insulin Insulin Receptor Insulin Resistance Kidney Kidney Diseases Laboratories Location Messenger RNA Mineralocorticoid Receptor Mineralocorticoids Modeling Molecular Na(+)-K(+)-Exchanging ATPase Natriuresis Obesity PPAR gamma Partner in relationship Pathology Pattern Phosphorylation Plasma Play Process Protein Tyrosine Kinase Proteins Range Rattus Receptor Signaling Regulation Relative (related person)Renal Hypertension Renal tubule structure Renin Renin-Angiotensin-Aldosterone System Research Personnel Role Series Signal Transduction Signaling Protein Sodium Sodium Channel Sodium Chloride Steroids System Testing Up-Regulation Vasopressins Water Week Zucker Rats age related aged blood pressure regulation candesartan day design dietary restriction epithelial Na+ channel mRNA Expression prevent programs protein expression receptor receptor binding receptor expression response rosiglitazone saluretic thiazide water channel

项目摘要

Obesity and insulin resistance are associated with hypertension. Inappropriate retention of sodium by the kidney is likely to play a major role. We previously showed that the obese Zucker rat (a model for these disorders) have increased renal protein abundance for three major sodium transport proteins: the alpha-1 subunit of Na-K-ATPase, the thiazide-sensitive NaCI cotransporter (NCC or TSC) and the beta-subunit of the epithelial sodium channel (ENaC). In contrast, as, they aged, obese rats developed renal hypertrophy along with diabetes and had a relative decrease in many important salt and water transport proteins, as compared to age-matched controls. We suggest that dysregulation of several important hormone systems in sodium balance may play a role in both alterations in sodium transport protein expression, as well as, the rapid develop of nephropathy. Candidate systems include the renin-angiotensin-aldosterone system (RAAS) and insulin (and or insulin resistance). We hypothesize that dysregulation of major sodium transport proteins of the kidney in the obese Zucker rat with age, is due at least in part to increased RAAS activity, and hyperinsulinemia, which in combination, result in inappropriate sodium retention and elevated blood pressure. Our specific aims include: 1) to determine if angiotensin II ATla receptor expression, binding, and activity is upregulated in the obese Zucker rat and whether this upregulation plays a role in changes in renal sodium transporter regulation, blood pressure, and renal hypertrophy; 2) to determine if enhanced mineratocorticoid receptor (MR) activity plays a role in increased whole kidney protein abundance of the thiazide-sensitive NaCI cotransporter (NCC), blood pressure, and renal hypertrophy, in the obese Zucker rat; 3) to determine the cellular location and sensitivity of the renal insulin receptor in obese Zucker rats relative to lean age-mates; 4) to determine whether treatment of insulin resistance with a PPAR-gamma agonist will decrease relative renal protein abundance of NCC, beta-ENaC, and Na-K-ATPase, as well as reduce blood pressure and renal hypertrophy in the obese Zucker rat, and whether these effects are reversed with short- term insulin infusion. These studies will allow us to determine the importance of each of these potential regulatory hormone systems in dyregulation of sodium transporter expression, sodium balance, and blood pressure in these obese rats.

肥胖和胰岛素抵抗与高血压有关。钠的不适当保留肾脏可能发挥重要作用。我们之前表明，肥胖的 Zucker 大鼠（这些大鼠的模型）疾病）增加了三种主要钠转运蛋白的肾蛋白丰度：α-1 Na-K-ATP 酶亚基、噻嗪类敏感的 NaCl 协同转运蛋白（NCC 或 TSC）和 β 亚基上皮钠通道（ENaC）。相比之下，随着年龄的增长，肥胖大鼠的肾脏随之出现肥大。与糖尿病患者相比，许多重要的盐和水转运蛋白相对减少到年龄匹配的控制。我们认为钠中几种重要激素系统的失调平衡可能在钠转运蛋白表达的改变以及快速钠转运蛋白表达的改变中发挥作用。发展为肾病。候选系统包括肾素-血管紧张素-醛固酮系统（RAAS）和胰岛素（和/或胰岛素抵抗）。我们假设主要钠转运蛋白的失调肥胖 Zucker 大鼠的肾脏随着年龄的增长，至少部分是由于 RAAS 活性增加，并且高胰岛素血症，两者结合起来会导致不适当的钠潴留和血液升高压力。我们的具体目标包括：1) 确定血管紧张素 II ATla 受体的表达、结合和肥胖 Zucker 大鼠的活性上调，以及这种上调是否在肾功能变化中发挥作用钠转运蛋白调节、血压和肾肥大； 2）判断是否增强盐皮质激素受体 (MR) 活性在增加全肾蛋白丰度中发挥作用肥胖 Zucker 大鼠中噻嗪类敏感的 NaCl 协同转运蛋白 (NCC)、血压和肾肥大； 3)确定肥胖Zucker相关大鼠肾胰岛素受体的细胞位置和敏感性依靠同龄人； 4) 确定用 PPAR-γ 激动剂治疗胰岛素抵抗是否会有效降低 NCC、β-ENaC 和 Na-K-ATP 酶的相对肾蛋白丰度，并减少血液肥胖 Zucker 大鼠的压力和肾肥大，以及这些影响是否可以通过短时间逆转定期胰岛素输注。这些研究将使我们能够确定这些潜力的重要性调节激素系统对钠转运蛋白表达、钠平衡和血液的失调这些肥胖老鼠的压力。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rosiglitazone regulates ENaC and Na-K-2Cl cotransporter (NKCC2) abundance in the obese Zucker rat.

Rosiglitazone 调节肥胖 Zucker 大鼠中的 ENaC 和 Na-K-2Cl 协同转运蛋白 (NKCC2) 丰度。

DOI：
发表时间：
2006
期刊：
影响因子：
4.2
作者：
Riazi, Shahla;Khan, Osman;Tiwari, Swasti;Hu, Xinqun;Ecelbarger, Carolyn A
通讯作者：
Ecelbarger, Carolyn A

Sex differences in adaptive downregulation of pre-macula densa sodium transporters with ANG II infusion in mice.

小鼠 ANG II 输注对致密斑前钠转运蛋白适应性下调的性别差异。

DOI：
发表时间：
2010-01
期刊：
影响因子：
0
作者：
Tiwari, Swasti;Li, Lijun;Riazi, Shahla;Halagappa, Veerendra K Madala;Ecelbarger, Carolyn M
通讯作者：
Ecelbarger, Carolyn M

Increased renal alpha-ENaC and NCC abundance and elevated blood pressure are independent of hyperaldosteronism in vasopressin escape.

肾脏 α-ENaC 和 NCC 丰度增加以及血压升高与加压素逃逸中醛固酮增多症无关。

DOI：
发表时间：
2006-07
期刊：
影响因子：
0
作者：
Tiwari, Swasti;Packer, Randall K;Hu, Xinqun;Sugimura, Yoshihisa;Verbalis, Joseph G;Ecelbarger, Carolyn A
通讯作者：
Ecelbarger, Carolyn A

17-beta Estradiol attenuates streptozotocin-induced diabetes and regulates the expression of renal sodium transporters.

17-β 雌二醇可减轻链脲佐菌素诱导的糖尿病并调节肾钠转运蛋白的表达。