Low-density lipoprotein receptor-related protein 2 (LRP2) (LRP2)

Low-density lipoprotein receptor-related protein 2 (LRP2), commonly known as megalin, is a large transmembrane endocytic receptor primarily expressed on the apical surface of proximal tubular epithelial cells in the kidney (UniProt: P98164). It plays a vital role in the reabsorption of a wide variety of filtered ligands, including proteins (such as albumin and hemoglobin), vitamins (such as Vitamin D and B12), and hormones, thereby preventing their loss in the urine (Christensen, E. I., et al., 2012, Nat. Rev. Nephrol.). Beyond its physiological role in nutrient recovery, megalin is a major mediator of drug-induced nephrotoxicity, as it facilitates the cellular uptake and accumulation of nephrotoxic agents like aminoglycoside antibiotics, polymyxins, and cisplatin (Schuh, C. D., et al., 2018, Nephrol. Dial. Transplant.). Mutations in the LRP2 gene result in Donnai-Barrow syndrome, a multi-system disorder characterized by renal protein loss and developmental defects (Kantarci, S., et al., 2007, Nat. Genet.). In the context of drug development, megalin is being investigated as a target for competitive inhibitors to prevent nephrotoxicity and as a portal for the targeted delivery of therapeutic agents to the renal proximal tubules (Saito, A., et al., 2010, J. Am. Soc. Nephrol.).

Other names

MegalinGlycoprotein 330gp330LRP-2

Megalin acts as a multi-ligand endocytic receptor that binds to various substances in the glomerular filtrate and internalizes them via clathrin-coated pits for transport to lysosomes (Christensen, E. I., & Nielsen, R., 2007, Rev. Physiol. Biochem. Pharmacol.). Drugs like aminoglycosides and cisplatin bind to the extracellular domain of megalin, triggering endocytosis and subsequent accumulation within proximal tubular cells, which leads to nephrotoxicity (Schuh, C. D., et al., 2018, Nephrol. Dial. Transplant.).