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

Abstract

Megalin has previously been shown to bind and mediate endocytosis of transcobalamin (TC)-B12. However, the physiological significance of this has not been established, and other TC-B12binding 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 B12and for renal accumulation of this highly conserved vitamin. Megalin-deficient mice excrete increased amounts of TC and B12in the urine, revealing a defective renal tubular uptake of TC-B12. The urinary B12excretion is increased ∼4-fold, resulting in an ∼28-fold higher renal B12clearance. This is associated with an ∼4-fold decrease in B12content in megalin-deficient kidney cortex. Thus megalin is important to prevent urinary loss of vitamin B12. In addition, light- and electron-microscopic immunocytochemistry demonstrate lysosomal accumulation of B12in rat and mouse proximal tubules. In rats this accumulation is correlated with vitamin intake. Thus renal lysosomal B12accumulation is dependent on vitamin status, indicating a possible reserve function of this organelle in the rat kidney.