Renal Sodium Transport in the Obese Zucker Rat

肥胖 Zucker 大鼠的肾钠转运

• 批准号: 7073450
• 负责人: Carolyn Mary Ecelbarger
• 金额: $ 30.31万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 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/7073450
• 关键词: aging; aldosterone; angiotensin receptor; corticosteroid receptors; hormone regulation /control mechanism; hypertension; in situ hybridization; insulin; insulin receptor; insulin sensitivity /resistance; kidney disorder chemotherapy; kidney hypertrophy; laboratory rat; membrane transport proteins; nonhuman therapy evaluation; obesity; peroxisome proliferator activated receptor; protein localization; receptor binding; receptor expression; renal tubular transport; renin angiotensin system; saluresis; sodium channel; sodium ion; sodium potassium exchanging ATPase

DESCRIPTION (provided by applicant): 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 At1a 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 mineralocorticoid 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.

描述（由申请人提供）： 肥胖和胰岛素抵抗与高血压有关。肾脏对钠的不适当潴留可能起着重要作用。我们之前表明，肥胖 Zucker 大鼠（这些疾病的模型）增加了三种主要钠转运蛋白的肾蛋白丰度：Na-K-ATP 酶的 α-1 亚基、噻嗪类敏感的 NaCl 协同转运蛋白（NCC 或 TSC）和上皮钠通道 (ENaC) 的 β 亚基。相比之下，随着年龄的增长，肥胖大鼠出现肾肥大和糖尿病，并且与年龄匹配的对照组相比，许多重要的盐和水转运蛋白相对减少。我们认为钠平衡中几种重要激素系统的失调可能在钠转运蛋白表达的改变以及肾病的快速发展中发挥作用。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）。我们推测，随着年龄的增长，肥胖 Zucker 大鼠肾脏主要钠转运蛋白的失调，至少部分是由于 RAAS 活性增加和高胰岛素血症，两者结合起来，导致不适当的钠潴留和血压升高。我们的具体目标包括：1) 确定肥胖 Zucker 大鼠中血管紧张素 II At1a 受体的表达、结合和活性是否上调，以及这种上调是否在肾钠转运调节、血压和肾肥大的变化中发挥作用； 2) 确定增强的盐皮质激素受体 (MR) 活性是否在肥胖 Zucker 大鼠中噻嗪类敏感性 NaCl 协同转运蛋白 (NCC) 的全肾蛋白丰度增加、血压和肾肥大中发挥作用； 3) 确定肥胖 Zucker 大鼠相对于瘦同龄大鼠肾胰岛素受体的细胞位置和敏感性； 4) 确定用PPAR-γ激动剂治疗胰岛素抵抗是否会降低NCC、β-ENaC和Na-K-ATP酶的相对肾蛋白丰度，以及降低肥胖Zucker大鼠的血压和肾肥大，以及短期胰岛素输注是否可以逆转这些影响。这些研究将使我们能够确定这些潜在的调节激素系统在​​这些肥胖大鼠的钠转运蛋白表达、钠平衡和血压失调中的重要性。