Renal hypoxia in the development of glomerular fibrosis

慢性肾脏疾病(CKD)影响超过10%的美国成年人，其中许多人进展到末期。 处于肾衰竭阶段。肾小球纤维化发生在几乎所有类型的CKD的早期，如糖尿病和 高血压肾病。为了更好地了解慢性肾脏病的发生和发展，在这个项目中，我们研究了 肾小球纤维化的发展，特别是肾组织氧合和血流灌注的变化。 纤维化的发展。作为众多研究表明的肾脏纤维化和损伤的主要决定因素， 肾组织缺氧在肾小球纤维化中的作用还没有被严格的体内实验完全阐明。 在这个项目中，通过一个控制良好的大鼠纤维化模型，我们将使用 创新和精确的MRI技术，然后通过肾脏活检准确判断纤维化程度。 我们的初步研究发现，在核磁共振测量的灌流和氧合显着下降的大鼠 中度肾小球纤维化。在拟议的项目中，我们将把我们的磁共振成像方案从当前的临床 MRI扫描仪到专用的7T小动物扫描仪，以进一步提高测量精度，并执行 轻度肾小球纤维化大鼠(纤维化诱导后1~4天)的MRI和活检结果。 在这个项目完成后，我们将更好地了解肾小球纤维化与 组织氧合/灌流，从而深入了解CKD的发病机制。有了在 目前的项目，在未来的研究中，我们将跟踪糖尿病患者的MRI测量的生理参数 与微量白蛋白尿(糖尿病肾病的高危因素)的关系，并验证这些参数的预测能力 糖尿病肾病。

Chronic kidney diseases (CKD) affect more than 10% of adult Americans, many of whom progress into end- stage renal failure. Glomerular fibrosis occurs in early stage of virtually all types of CKD, such as diabetic and hypertensive nephropathy. To better understand the initiation and progression of CKD, in this project we study the development of glomerular fibrosis, specifically the changes of renal tissue oxygenation and perfusion in the fibrotic development. As a major determinant for renal fibrosis and injury suggested by numerous studies, renal tissue hypoxia’s role in glomerular fibrosis has not been fully elucidated with rigorous in-vivo experiments. In this project with a well-controlled rat-fibrosis model, we will measure tissue oxygenation and perfusion using innovative and precise MRI techniques, and then accurately determine the fibrosis degree by kidney biopsy. Our preliminary study found significant decreases in MRI-measured perfusion and oxygenation in rats with intermediate glomerular fibrosis. In the proposed project, we will transfer our MRI protocol from current clinical MRI scanner to a dedicated 7T small-animal scanner to further improve measurement precision, and perform the MRI and biopsy measurements on rats with mild glomerular fibrosis (days 1 to 4 after fibrosis induction). Upon completion of this project, we will understand better the relationship between glomerular fibrosis and tissue oxygenation/perfusion, and thus gain insight into the initiation of CKD. With the knowledge gained in the current project, in future studies we will track the MRI-measured physiologic parameters for diabetic patients with microalbuminuria (high risk for diabetic nephropathy), and validate the parameters’ capability in predicting diabetic nephropathy.