Renal Sodium Transport in the Obese Zucker Rat

肥胖和胰岛素抵抗与高血压有关。钠的不适当保留 肾可能起主要作用。我们先前表明，肥胖的Zucker大鼠（这些模型） 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酶的β-亚基、噻嗪敏感性NaCl协同转运蛋白（NCC或TSC）和 上皮钠通道（ENaC）。相反，随着年龄的增长，肥胖大鼠沿着肾脏肥大 与糖尿病患者相比， 年龄匹配的对照组。我们认为，在钠离子缺乏的情况下， 平衡可能在钠转运蛋白表达的改变中起作用， 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（或胰岛素抵抗）。我们推测，主要的钠转运蛋白的失调， 肥胖Zucker大鼠的肾脏随年龄增长，至少部分是由于RAAS活性增加， 高胰岛素血症，其组合导致不适当钠潴留和升高的血液 压力我们的具体目标包括：1）确定血管紧张素II AT 1a受体的表达、结合和 活动在肥胖Zucker大鼠中上调，以及这种上调是否在肾功能的变化中起作用， 钠转运蛋白调节、血压和肾肥大; 2）确定是否增强 盐皮质激素受体（MR）活性在增加全肾蛋白丰度中起作用， 肥胖Zucker大鼠中噻嗪敏感性NaCl协同转运蛋白（NCC）、血压和肾脏肥大; 3)确定肥胖Zucker大鼠肾脏胰岛素受体的细胞定位和敏感性 4）确定用PPAR-gamma激动剂治疗胰岛素抵抗是否会 降低NCC、beta-ENaC和Na-K-ATP酶的相对肾蛋白丰度，以及降低血液 压力和肾脏肥大的肥胖Zucker大鼠，以及这些影响是否被逆转与短- 长期胰岛素输注。这些研究将使我们能够确定这些潜力中的每一个的重要性 钠转运蛋白表达、钠平衡和血液调节异常中的调节激素系统 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.