Renal Sodium Transport in the Obese Zucker Rat

肥胖和胰岛素抵抗与高血压有关。不适当地保留钠 肾脏可能起主要作用。我们之前证明了肥胖的Zucker大鼠(这些动物的模型 疾病)增加了肾脏三种主要钠转运蛋白的蛋白丰度：α-1 Na-K-ATPase的亚基，对硫氮化物敏感的NaCI共转运体(NCC或TSC)和 上皮钠通道(ENaC)。相反，随着年龄的增长，肥胖大鼠出现肾脏肥大 与糖尿病患者相比，许多重要的盐和水运输蛋白相对减少 年龄匹配的对照组。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 肾病的发生发展。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 肥胖的Zucker大鼠的肾脏随着年龄的增长，至少部分是由于RAAS活性的增加，以及 高胰岛素血症，两者结合在一起，会导致不适当的钠滞留和血液升高 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 肥胖的Zucker大鼠的活性上调以及这种上调是否在肾脏的变化中起作用 钠转运体调节、血压和肾脏肥大；2)确定是否增强 盐皮质激素受体(MR)活性在小鼠全肾蛋白丰度增加中起作用 在肥胖的Zucker大鼠中，对硫氮化物敏感的NaCI协同转运体(NCC)、血压和肾脏肥大； 3)测定肥胖Zucker大鼠肾脏胰岛素受体的细胞定位和敏感性。 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-ATPase的相对肾脏蛋白丰度，并减少血液 肥胖的Zucker大鼠的血压和肾脏肥厚，以及这些影响是否被Short-Th逆转 定期胰岛素输注。这些研究将使我们能够确定每一种潜力的重要性 钠转运体表达、钠平衡和血液调节失调的激素系统 这些肥胖大鼠体内的压力。

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.