Renal Sodium Transport in the Obese Zucker Rat

描述(由申请人提供)： 肥胖和胰岛素抵抗与高血压有关。肾脏对钠的不适当滞留可能起到重要作用。我们以前发现肥胖的Zucker大鼠(这些疾病的模型)增加了肾脏三种主要钠转运蛋白的蛋白丰度：Na-K-ATPase的α-1亚单位、对硫氮化物敏感的NaCI共转运体(NCC或TSC)和上皮钠通道的β亚单位(ENaC)。相比之下，随着年龄的增长，肥胖大鼠出现肾脏肥大并伴有糖尿病，与年龄匹配的对照组相比，许多重要的盐和水运输蛋白相对减少。我们认为钠平衡中几个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起作用。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，肥胖的Zucker大鼠肾脏主要钠转运蛋白随年龄增长而失调，至少部分原因是RAAS活性增加，以及高胰岛素血症，两者相结合，导致不适当的钠滞留和血压升高。我们的具体目标包括：1)确定肥胖的Zucker大鼠血管紧张素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脏钠转运体调节、血压和肾脏肥大的变化中发挥作用；2)确定盐皮质激素受体(MR)活性增强是否在肥胖Zucker大鼠全肾蛋白丰度增加的硫氮化物敏感的NaCI辅助转运体(NCC)、血压和肾脏肥大中起作用；3)确定肥胖Zucker大鼠肾脏胰岛素受体的细胞位置和敏感性；4)确定PPAR-γ激动剂治疗胰岛素抵抗是否会降低肥胖Zucker大鼠肾脏NCC、β-ENaC和Na-K-ATPase的相对蛋白丰度，降低血压和肾脏肥大，以及短期胰岛素注射是否能逆转这些作用。这些研究将使我们能够确定这些潜在的调节激素系统中的每一个在这些肥胖大鼠钠转运体表达、钠平衡和血压调节失调中的重要性。

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.