Renal hypoxia in the development of glomerular fibrosis

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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.