Molecular mechanisms of receptor-mediated endocytosis in the renal proximal tubular epithelium

Abstract

Receptor-mediated endocytosis is a pivotal function of renal proximal tubule epithelial cells (PTECs) to reabsorb and metabolize substantial amounts of proteins and other substances in glomerular filtrates. The function accounts for the conservation of nutrients, including carrier-bound vitamins and trace elements, filtered by glomeruli. Impairment of the process results in a loss of such substances and development of proteinuria, an important clinical sign of kidney disease and a risk marker for cardiovascular disease. Megalin is a multiligand endocytic receptor expressed at clathrin-coated pits of PTEC, playing a central role in the process. Megalin cooperates with various membrane molecules and interacts with many intracellular adaptor proteins for endocytic trafficking. Megalin is also involved in signaling pathways in the cells. Megalin-mediated endocytic overload leads to damage of PTEC. Further studies are needed to elucidate the mechanism of megalin-mediated endocytosis and develop strategies for preventing the damage of PTEC.

Figure 1

Megalin and its associated molecules involved in receptor-mediated endocytosis in PTEC. On the apical membrane of PTEC, various molecules are involved in the process of receptor-mediated endocytosis. Megalin, playing a central role in the process, cooperates with other membrane proteins such as the cubilin-amnionless complex (CUBAM), NHE3, and ClC5. Megalin and CUBAM directly bind a variety of ligands, whereas NHE3 and ClC5 are involved in endosomal acidification, which is important for further processing of endocytosed proteins. Megalin also interacts with intracellular adaptor proteins such as ARH, Dab2, and GIPC. Dab2 binds to motor proteins, myosin VI, and NMHC IIA, which may mediate endocytic trafficking of the molecular complexes through actin filaments. The cytoplasmic tail of megalin is released from the membrane by γ-secretase and is involved in intracellular signal transduction.