Megalin Receptor

In the kidney, megalin is expressed on the luminal surface of the renal proximal tubules, a tissue responsible for retrieval of essential metabolites filtered through the glomerulus. Filtration of plasma in the kidney produces approximately 180 litres of ultra filtrate every day. The ultra filtrate contains waste products and metabolites destined for excretion in the urine, but it also contains many essential substances such as proteins, vitamins, hormones, ions and water. The latter substances are important for the body and must be recycled in the kidney to prevent uncontrolled urinary loss, which would otherwise result in multiple and severe defects including salt wasting, anemia and bone disease. Recycling of essential metabolites in the kidney is mediated by a number of active and passive absorption processes in the proximal tubules (Figure 2).

Studies using knockout animals lacking the megalin gene have demonstrated that this receptor is an important component of the retrieval machinery in the kidney. As megalin knockout animals do not have the receptor in the kidney, they suffer from low molecular weight proteinuria, loosing a large amount of small proteins in the urine. They also excrete elevated levels of important vitamins and steroid hormones including vitamins A and D.

Megalin is abundantly expressed on the surface of the cells lining the proximal tubules in the kidney. Binding of ligands to megalin, results in endocytosis of the bound components. Following endocytosis, the bound ligands are transported to lysosomes where protein components are degraded into amino acids while vitamins and steroid hormones bound to the proteins are released and recycled into the blood stream (Figure 2).

As megalin is such an efficient retrieval pathway for substances from the glomerular filtrate into the kidney, this pathway is also responsible for renal uptake of substances that are foreign to the body (xenobiotics). Many xenobiotics such as therapeutic drugs or environmental toxins are also cleared from the blood stream by glomerular filtration. However, rather than being excreted into the urine, some of the substances accidentally bind to megalin because they exhibit positive charges. Thus, they abuse this retrieval pathway to enter the kidney where they accumulate and cause severe damage to the tissue (nephrotoxicity). A similar role for megalin in inner ear uptake and ototoxicity of some drugs are also proposed.