We usually associate proteinuria with a defect in the glomerular filtration barrier, but it is useful to remember that the proximal tubule (PT) also plays a role in resorption of proteins. Nate discussed this controversy in a prior post. In equilibrium, small amounts of low molecular weight (LMW) proteins are filtered through the normal glomerulus. Once in the PT, two receptors called megalin (a member of the LDL receptor family) and cubulin are responsible for resorption of those filtered proteins, resulting in a virtually protein-free ultrafiltrate. A third protein, amnionless (AMN) also plays a critical role by escorting cubulin to the cell membrane surface. The megalin-cubulin-AMN receptor complex is able to bind to a variety of LMW proteins and internalize them within PT cells, where they are broken down inside lysosomes. Interestingly, cubulin was initially discovered to bind intrinsic factor-B12, and deficiencies in cubulin lead to B12 malabsorption (see below).
Defects in megalin-cubulin-AMN mediated protein endocytosis are responsible for several clinical syndromes, listed below:
- Dent’s disease – is an X-linked defect in a Cl-/H+ exchanger expressed in the proximal tubules and collecting duct intercalated cells. Cl-/H+ knockout mice have very low levels of cubulin and megalin expression, which would explain the LMW proteinuria seen in affected patients. It is less clear how the defect causes PT damage leading to the aminoaciduria, glycosuria, phosphaturia, and hypercalciuria that characterize this disease.
- DB/FOAR syndrome – a genetic defect in LDL receptor protein 2 encoding megalin results in a lack of functional megalin. The syndrome leads to hypertelorism, myopia, hearing loss, and proteinuria, along with many defects in fetal development. If you really wanted to know, DB/FOAR stands for Donnai-Barrow/facio-oculo-acoustico-renal syndromes, described separately but now known to be the same entity.
- Gräsbeck-Imerslund disease – a autosomal recessive defect in either cubulin or AMN synthesis, these patients present with megaloblastic anemia (cubulin deficiency leads to selective B12 malabsorption, as mentioned above) and proteinuria.