The kidney in vitamin B₁₂and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins

Abstract

Over the past 10 years, animal studies have uncovered the molecular mechanisms for the renal tubular recovery of filtered vitamin and vitamin carrier proteins. Relatively few endocytic receptors are responsible for the proximal tubule uptake of a number of different vitamins, preventing urinary losses. In addition to vitamin conservation, tubular uptake by endocytosis is important to vitamin metabolism and homeostasis. The present review focuses on the receptors involved in renal tubular recovery of folate, vitamin B12, and their carrier proteins. The multiligand receptor megalin is important for the uptake and tubular accumulation of vitamin B12. During vitamin load, the kidney accumulates large amounts of free vitamin B12, suggesting a possible storage function. In addition, vitamin B12 is metabolized in the kidney, suggesting a role in vitamin homeostasis. The folate receptor is important for the conservation of folate, mediating endocytosis of the vitamin. Interaction between the structurally closely related, soluble folate-binding protein and megalin suggests that megalin plays an additional role in the uptake of folate bound to filtered folate-binding protein. A third endocytic receptor, the intrinsic factor-B12 receptor cubilin-amnionless complex, is essential to the renal tubular uptake of albumin, a carrier of folate. In conclusion, uptake is mediated by interaction with specific endocytic receptors also involved in the renal uptake of other vitamins and vitamin carriers. Little is known about the mechanisms regulating intracellular transport and release of vitamins, and whereas tubular uptake is a constitutive process, this may be regulated, e.g., by vitamin status.

Age-Related Alterations of B-Group Vitamin Contents in Urine, Blood and Liver from Rats

“…Vitamin B12 is different from other Bgroup vitamin because of its mechanism of absorption. Free vitamin B12 binds with haptocorrin and gastric intrinsic factor (IF) in the stomach and the duodenum, respectively, and this IF-vitamin B12 complex attaches to the intestinal IF-vitamin B12 receptor in the ileal mucosa, and vitamin B12 enters the enterocyte (28). The high prevalence of mild cobalamin deficiency in healthy older subjects can be partly explained by inadequate vitamin B12 intake or severe atrophic gastritis (29).…”

“…Interestingly, the urinary recovery rate of vitamin B12 dramatically increased to 130% at 80 wk old. Vitamin B12 binds to carrier protein transcobalamin (TC) in serum (30), and TC-vitamin B12 complex is reabsorbed in the proximal convoluted tubule via a receptor-mediated system (28). Megalin is an essential receptor for reabsorption of TC-vitamin B12 complex in the proximal tubule (31).…”

Urinary Water-Soluble Vitamins as Nutritional Biomarker to Estimate Their Intakes

“…These results suggest that the change in the level of urinary vitamin B 12 is too small to evaluate intake of vitamin B 12 , and thus urinary vitamin B 12 was unavailable to be used as biomarker for estimation of its intake. To excrete vitamin B 12 into urine, vitamin B 12 binds to carrier protein transcobalamin (TC) in serum (Allen, 1975), the TC-vitamin B 12 complex is filtered in the glomeruli, and the proximal convoluted tubule reabsorbs this complex via a receptormediated system (Birn, 2006). Megalin is an essential receptor for reabsorption of the TCvitamin B 12 complex in the proximal tubule (Birn et al, 2002), binds to the TC-vitamin B 12 complex with an estimated affinity (K d ) of ~183 nmol/L (Moestrup et al, 1996).…”

Vitamin B12 Deficiency In Chronic Kidney Disease

“…The B 12 -IF complex is absorbed in the ileum via the cubilin receptor [11]. Defects in cubilin, a proximal tubular membrane protein, have been associated with both megaloblastic anemia and tubular proteinuria [11][12][13][14]. Cubilin also acts to reabsorb the majority of filtered albumin from the urine and recently, genome-wide association studies have identified SNPs in CUBN in association with albuminuria [15] and B 12 levels [16,17].…”