Chronic kidney disease (CKD) is associated with increased cardiovascular disease (CVD) risk and mortality, yet the underlying mechanisms are unknown. The large endocytic receptor low-density lipoprotein-related protein 2 (LRP2) is important for renal function and genetic deficiencies result in CKD. In this project, I aim to explore the correlation of LRP2 O-glycosylation to human CKD and CVD progression and dissect the underlying mechanisms by which insufficiently glycosylated LRP2 could cause CKD.
Exploring the role of LRP2 O-glycosylation in maintaining renal and cardiovascular homeostasis
Cardiovascular disease (CVD) is a world-wide major cause of death and the risk of developing CVD is highly potentiated by chronic kidney disease (CKD). The glycoprotein LRP2, also known as megalin, is highly expressed in renal proximal tubule cells. LRP2 is a key player for the reabsorption and clearance of numerous ligands from the tubular fluid and dysfunction of LRP2 and genetic deficiencies lead to CKD. Moreover, genome-wide association studies link the glycosylating enzyme (GALNT11) to CKD in humans.
We recently discovered that LRP2 carries glycans in the extracellular ligand-binding domain and that loss of these glycans affect ligand binding and result in kidney disease in animal models.
To correlate the level of LRP2 O-glycosylation to human kidney disease and cardiovascular homeostasis and explore the biological and functional consequences of LRP2 glycosylation in cell and animal models.
We will employ a mass spectrometry (MS)-based strategy including parallel-reaction monitoring (PRM) analysis to evaluate and quantify LRP2-derived peptides and glycopeptides in urine samples from a large CKD cohort. In parallel we will examine the roles of GALNT11 in LRP2 receptor function in established cell lines and validate our collective findings in vivo by visualizing the uptake of fluorescently conjugated ligands in conditional Galnt11 knockout mice using intravital microscopy.
We expect to provide insights into the basic biology of renal LRP2 and mechanisms underlying cardiorenal syndrome and to identify novel therapeutic intervention targets.
Associate Professor Katrine T. Schjoldager, University of Copenhagen, Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine
Christina Christoffersen, MD, PhD, University of Copenhagen, Department of Clinical Biochemistry
Robert Weigert, PhD, senior investigator, National Institute of Health, Laboratory of Cellular & Molecular Biology, US