GLOMERULAR AND TUBULAR FUNCTION IN THE DIABETIC KIDNEY

糖尿病是美国终末期肾病的主要原因。 早期糖尿病的特征是肾小球超滤和肾脏体积增大。此外，糖尿病改变了肾血管对各种生理刺激的反应，包括灌注压、盐摄入和蛋白质喂养的变化。 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，但对这些异常的基本原因知之甚少。 本研究的主要目的是探讨链脲佐菌素糖尿病大鼠肾脏血流动力学异常的基础。 该模型将通过各种显微穿刺和体外技术进行研究。 注意力将集中在肾小球和近端小管之间的相互作用，并对负责糖尿病肾脏的矛盾反应饮食中的盐和其他刺激的变化的介质。沿着，研究将涉及三个具体目标。 第一个目的是发现糖尿病肾小球超滤是否是肾小管肾小球反馈（TGF）改变的结果。 这将通过确定超滤的开始是否需要使TGF失活的近端重吸收的先前增加，通过评估降低的TGF效率对超滤的贡献，以及通过检查糖尿病是否改变TGF适应肾小管功能变化的方式来实现。 第二个目的是解释饮食限盐加剧糖尿病高滤过和肥大的矛盾趋势。 据推测，这种基本的异常涉及竞争性血管收缩剂和血管扩张剂之间的失衡，每种都在限盐期间被激活。 注意力将集中在调节肾素-血管紧张素和一氧化氮系统的能力，以及在控制近端肾小管生长和功能中饮食盐和糖尿病之间的相互作用。 第三个目的是了解糖尿病患者血管紧张素转换酶抑制剂（ACEI）对肾脏血流动力学影响的机制。研究将集中于缓激肽、七肽ANG（1-7）和替代ANG II第二信使系统（NADH/NADPH氧化酶和血红素加氧酶）的作用。 了解为什么ACEI使糖尿病肾脏能够调节其内部血流动力学，将提供深入了解的机制，在糖尿病患者中的有益作用，并进入糖尿病状态的病理生理。

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.