The large (∼600 kDa) endocytosis receptor megalin/low-density lipoprotein receptor-related protein 2 is highly expressed at the apical membrane of proximal tubular epithelial cells (PTECs). Megalin plays an important role in the endocytosis of various ligands via interactions with intracellular adaptor proteins, which mediate the trafficking of megalin in PTECs. Megalin mediates the retrieval of essential substances, including carrier-bound vitamins and elements, and impairment of the endocytic process may result in the loss of those substances. In addition, megalin reabsorbs nephrotoxic substances such as antimicrobial (colistin, vancomycin, and gentamicin) or anticancer (cisplatin) drugs and advanced glycation end product-modified or fatty acid-containing albumin. The megalin-mediated uptake of these nephrotoxic ligands causes metabolic overload in PTECs and leads to kidney injury. Blockade or suppression of the megalin-mediated endocytosis of nephrotoxic substances may represent a novel therapeutic strategy for drug-induced nephrotoxicity or metabolic kidney disease. Megalin reabsorbs urinary biomarker proteins such as albumin, α1-microglobulin, β2-microglobulin, and liver-type fatty acid-binding protein; thus, the above-mentioned megalin-targeted therapy may have an effect on the urinary excretion of these biomarkers. We have previously established a sandwich enzyme-linked immunosorbent assay to measure the ectodomain (A-megalin) and full-length (C-megalin) forms of urinary megalin using monoclonal antibodies against the amino- and carboxyl-terminals of megalin, respectively, and reported their clinical usefulness. In addition, there have been reports of patients with novel pathological anti-brush border autoantibodies targeting megalin in the kidney. Even with these breakthroughs in the characterization of megalin, a large number of issues remain to be addressed in future research.

anti-brush border antibody

ankyrin-repeat family A protein

apical recycling endosome

autosomal recessive hypercholesterolemia

apical sorting endosomes

chronic kidney disease

common recycling endosome

diabetic kidney disease

Donnai-Barrow syndrome

fluid-phase endocytosis

G alpha interacting protein-interacting protein-C-terminus

low-density lipoprotein

Madin-Darby canine kidney

type IIa sodium phosphate co-transporter

Na+-H+ exchanger regulatory factor

O-linked β-N-acetylglucosamine modification

proximal tubular epithelial cells

receptor-mediated endocytosis

sodium glucose cotransporter

Endocytosis

Megalin

Nephrotoxicity

Proximal tubule

Trafficking

© 2023 The Authors. Published by Elsevier Ltd.