Imaging Mass Spectrometry for the Elucidation of Lipid and Protein Changes in Diabetic Nephropathy and Assessment of Drug Efficacy

Abstract

Diabetic nephropathy (DN) leads to progressive decline in renal function and is the leading cause of end-stage renal disease. Much still remains unknown about the pathogenesis of this disease. This project investigates the molecular changes that take place in kidney glomeruli and tubules to explore the pathogenic mechanisms of this disease by use of matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS). MALDI IMS is a molecular imaging technology that provides the spatial distribution and relative abundance of hundreds of analytes directly from a tissue section. Methods for direct tissue analysis of individual glomeruli and tubules within the kidney cortex by high spatial resolution imaging mass spectrometry and histology directed profiling techniques are presented. These methods are then applied to an experimental mouse model of human DN. In this work, changes in different classes of biomolecules including proteins and lipids have been investigated with specific signatures found in diseased and healthy kidneys. Additionally, the response of these lipids and proteins was investigated after administration of a drug candidate that is being evaluated for the treatment of DN. High spatial resolution IMS provides a powerful tool to detect protein and lipid modifications associated with diabetic nephropathy from specific structures within the renal cortex. Determining biomolecules that undergo change in disease conditions and evaluating response to treatment may lead to new molecular markers of disease, provide insight into disease pathogenesis, and characterize treatment response.