Glomerular and Tubular Function in the Diabetic Kidney

描述(申请人提供)：糖尿病是发达国家终末期肾病最常见和增长最快的原因。大多数正在进行的对糖尿病肾脏的实验室和临床研究主要集中在糖尿病15-20年后开始的损伤和疤痕。然而，早期血流动力学表型导致糖尿病肾脏随后死亡的最初想法继续证明人们对糖尿病早期阶段的兴趣是合理的。早期糖尿病的特征是肾小球高滤过和肾脏增大。早期糖尿病还会改变肾血管对各种生理刺激的反应，包括灌注压、盐摄入量、蛋白质摄入量和外源性胰岛素的变化。虽然肾内血流动力学异常在糖尿病肾病的发病机制中具有潜在的关键作用，但这些异常的根本原因却知之甚少。这项研究的主要目的是了解在糖尿病开始时发生的主要肾脏血流动力学异常，远在肾脏损害开始之前。这一竞争性更新的基础是在上一次供资期间所作的观察。一个中心主题是，早期糖尿病患者肾小球功能的明显异常通常代表肾小球对Henley近端小管或环的原发异常的生理反应，这些异常通过致密斑区反馈影响肾小球。利用早期链脲佐菌素糖尿病大鼠和小鼠，通过肾脏显微穿刺法获得肾单位功能的数据，通过激光捕获显微切割和定量RT-PCR获得功能基因组学数据，并通过免疫组织化学方法获得蛋白质表达的数据。具体目标是：1)回答有关推动早期糖尿病肾脏生长的因素的关键问题，以及2)回答有关早期糖尿病中发生的肾小管重吸收的特性以及肾小管和肾小球之间的功能相互作用的关键问题。

DESCRIPTION (provided by applicant): Diabetes mellitus is the commonest and fastest growing cause of end-stage renal disease in the developed world. Most ongoing laboratory and clinical research into the diabetic kidney focuses on injury and scarring that begin after 15-20 years of diabetes. However, the original idea that an early hemodynamic phenotype provokes the subsequent demise of a diabetic kidney continues to justify interest in the earlier stages of diabetes. Early diabetes is characterized by both glomerular hyper filtration and increased kidney size. Early diabetes also modifies the renal vascular response to a variety of physiologic stimuli including changes in perfusion pressure, salt intake, protein feeding, and exogenous insulin. While intrarenal hemodynamic abnormalities are potentially critical to the pathogenesis of diabetic nephropathy, the elemental cause of these abnormalities is poorly understood. It is the main purpose of this research to understand the cardinal renal hemodynamic abnormalities that occur at the start of diabetes, long before the onset of kidney damage. The foundation for this competing renewal rests on observations made during the last funding period. A central theme is that apparent abnormalities of glomerular function in early diabetes often represent a physiologic response of the glomerulus to primary abnormalities in the proximal tubule or loop of Henley that impact the glomerulus by feedback through the macula densa. Utilizing rats and mice with early streptozotocin diabetes, data will be obtained on nephron function by renal micropuncture, on functional genomics by laser capture micro dissection followed by quantitative RTPCR, and on protein expression by immunohistochemistry. The Specific Aims are: 1) To answer key questions regarding factors that drive kidney growth in early diabetes, and 2) To answer key questions regarding peculiarities of tubular reabsorption and the functional interactions between the tubule and glomerulus that occur in early diabetes.