GLOMERULAR AND TUBULAR FUNCTION IN THE DIABETIC KIDNEY

在美国，糖尿病是导致终末期肾脏疾病的主要原因。早期糖尿病以肾小球高滤过和肾脏增大为特征。此外，糖尿病会改变肾血管对各种生理刺激的反应，包括灌注压、盐摄入量和蛋白质摄食的变化。虽然肾内血流动力学异常对糖尿病肾病的发病机制可能至关重要，但这些异常的基本原因尚不清楚。本研究旨在探讨链脲佐菌素糖尿病大鼠肾血流动力学异常的基础。该模型将通过各种微穿刺和体外技术进行研究。关注将集中在肾小球和近端小管之间的相互作用，以及负责糖尿病肾脏对饮食盐和其他刺激变化的矛盾反应的介质。在此过程中，研究将针对三个具体目标。第一个目的是发现糖尿病肾小球高滤过是否是小管肾小球反馈（TGF）改变的结果。这将通过确定高滤的发生是否需要近端重吸收的事先增加而使TGF失活，通过评估TGF效率降低对高滤的贡献，以及通过检查糖尿病是否改变TGF适应小管功能变化的方式来实现。第二个目的是解释饮食盐限制加剧糖尿病超滤过和肥厚的矛盾倾向。这种基本的异常被认为与血管收缩剂和血管扩张剂之间的竞争不平衡有关，两者在限盐期间都被激活。关注将集中在调节肾素-血管紧张素和一氧化氮系统的能力，以及饮食盐和糖尿病之间在控制近端肾小管生长和功能方面的相互作用。第三个目的是了解血管紧张素转换酶抑制剂（ACEI）对糖尿病患者肾脏血流动力学影响的机制。研究将集中在缓激素、七肽ANG（1-7）和其他ANG II第二信使系统（NADH/NADPH氧化酶和血氧合酶）的作用上。理解ACEI使糖尿病肾脏能够调节其内部血流动力学的原因，将有助于深入了解ACEI对糖尿病患者有益作用的机制和糖尿病状态的病理生理学。

Diabetes mellitus is the leading cause of end-stage renal disease in the United States. Early diabetes is characterized by glomerular hyperfiltration and increased kidney size. Furthermore, diabetes alters the renal vascular response to a variety of physiologic stimuli including changes in perfusion pressure, salt intake, and protein feeding. 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 general purpose of the proposed research to examine the basis for the cardinal renal hemodynamic abnormalities in the rat with streptozotocin diabetes. This model will be studied by a variety of micropuncture and in vitro techniques. Attention will focus on interactions between the glomerulus and proximal tubule and on the mediators responsible for paradoxical reactions of the diabetic kidney to changes in dietary salt and other stimuli. Along the way, studies will address three specific aims. The first aim is to discover whether diabetic glomerular hyperfiltration is a consequence of altered tubuloglomerular feedback (TGF). This will be achieved by determining whether or not the onset of hyperfiltration requires a prior increase in proximal reabsorption which deactivates TGF, by assessing the contribution of decreased TGF efficiency to hyperfiltration, and by examining whether diabetes alters the way in which TGF adapts to changes in tubular function. The second aim is to explain the paradoxical tendency for dietary salt restriction to exacerbate diabetic hyperfiltration and hypertrophy. The basic abnormality is presumed to involve an imbalance between competing vasoconstrictors and vasodilators, each activated during salt restriction. Attention will focus on the ability to modulate the renin-angiotensin and nitric oxide systems and on interactions between dietary salt and diabetes in the control of proximal tubular growth and function. The third aim is to understand the mechanism(s) which underlie the renal hemodynamic effects of angiotensin converting enzyme inhibitors (ACEI) in diabetes. Studies will focus on the roles of bradykinin, the heptapeptide ANG (1-7), and alternative ANG II second messenger systems (NADH/NADPH oxidase, and hemoxygenase). Understanding why ACEI renders the diabetic kidney capable of modulating its internal hemodynamics will provide insight into the mechanisms which underlie the salutary effect of ACEI in diabetic patients and into the pathophysiology of the diabetic state.