Megalin is essential for renal proximal tubule reabsorption and accumulation of transcobalamin-B12

Megalin has previously been shown to bind and mediate endocytosis of transcobalamin (TC)-B-12. However, the physiological significance of this has not been established, and other TC-B-12 binding proteins have been suggested to mediate renal uptake of this vitamin complex. The present study demonstrates by the use of megalin-deficient mice that megalin is, in fact, essential for the normal renal reabsorption of TC-vitamin B-12 and for renal accumulation of this highly conserved vitamin. Megalin-deficient mice excrete increased amounts of TC and B-12 in the urine, revealing a defective renal tubular uptake of TC- B-12. The urinary B-12 excretion is increased similar to4-fold, resulting in an similar to28-fold higher renal B-12 clearance. This is associated with an similar to4-fold decrease in B-12 content in megalin-deficient kidney cortex. Thus megalin is important to prevent urinary loss of vitamin B-12. In addition, light- and electron-microscopic immunocytochemistry demonstrate lysosomal accumulation of B-12 in rat and mouse proximal tubules. In rats this accumulation is correlated with vitamin intake. Thus renal lysosomal B-12 accumulation is dependent on vitamin status, indicating a possible reserve function of this organelle in the rat kidney.