Diversity in rat tissue accumulation of vitamin B12 supports a distinct role for the kidney in vitamin B12 homeostasis

Nephrology Dialysis Transplantation, Jun 2003

Background. Vitamin B12 in plasma is complexed to the carrier proteins transcobalamin (TC) and haptocorrin. The TC–B12 complex is filtered in the glomeruli and reabsorbed in the renal tubules by receptor‐mediated endocytosis, providing a route for a significant renal accumulation of vitamin B12. The present study investigates the role of the rodent kidney in B12 homeostasis by examining the distribution of vitamin B12 in rats during vitamin B12 depletion or B12 load, and compares kidney accumulation with the vitamin distribution in other tissues including brain, liver, testes, intestine, spleen and plasma. Methods. Fifteen rats were fed on a diet containing different concentrations of B12 supplemented with s.c. injections of B12. Twenty four hours prior to sacrifice, all animals were injected with [57Co]B12. The vitamin contents of kidneys, liver, spleen, brain, testis, intestine, skeletal muscle, serum and urine were analysed. Both total tissue vitamin B12 accumulation and [57Co]B12 were determined to compare steady‐state B12 and the distribution of an acutely injected dose. In the kidney, free and protein‐bound B12 was determined by gel filtration. Results. The rat kidneys accumulated more B12 during normal and loaded conditions than any other tissue. A 110‐fold increase in vitamin content was observed from the deficient to the loaded conditions in the kidney compared with a 3.5‐fold increase in the liver. In contrast to all other organs, significantly smaller amounts of acutely injected B12 accumulated in the kidneys in the vitamin‐deprived state compared with both the normal and the vitamin‐loaded condition. Conclusions. The present study suggests a significant role for the rodent kidney in vitamin B12 metabolism. We propose a model for rat tissue uptake consistent with the presence of two different TC–B12 receptors and renal uptake following filtration of TC–B12 in the glomeruli. The presented model allows for the reduced renal uptake and accumulation in vitamin‐deprived conditions, thus reserving the vitamin for other tissues, including nerve tissue and bone marrow, which are more sensitive to vitamin B12 deficiency.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://ndt.oxfordjournals.org/content/18/6/1095.full.pdf

Diversity in rat tissue accumulation of vitamin B12 supports a distinct role for the kidney in vitamin B12 homeostasis

Henrik Birn 1 2 Ebba Nex 0 1 Erik Ils Christensen 1 2 Rikke Nielsen 1 2 0 Department of Clinical Biochemistry , AKH, Aarhus University Hospital , Aarhus, Denmark 1 Department of Cell Biology, Institute of Anatomy, University of Aarhus , Building 234, DK-8000 Aarhus C, Denmark 2 Department of Cell Biology, Institute of Anatomy, University of Aarhus Background. Vitamin B12 in plasma is complexed to the carrier proteins transcobalamin (TC) and haptocorrin. The TC-B12 complex is filtered in the glomeruli and reabsorbed in the renal tubules by receptormediated endocytosis, providing a route for a significant renal accumulation of vitamin B12. The present study investigates the role of the rodent kidney in B12 homeostasis by examining the distribution of vitamin B12 in rats during vitamin B12 depletion or B12 load, and compares kidney accumulation with the vitamin distribution in other tissues including brain, liver, testes, intestine, spleen and plasma. Methods. Fifteen rats were fed on a diet containing different concentrations of B12 supplemented with s.c. injections of B12. Twenty four hours prior to sacrifice, all animals were injected with [57Co]B12. The vitamin contents of kidneys, liver, spleen, brain, testis, intestine, skeletal muscle, serum and urine were analysed. Both total tissue vitamin B12 accumulation and [57Co]B12 were determined to compare steady-state B12 and the distribution of an acutely injected dose. In the kidney, free and protein-bound B12 was determined by gel filtration. Results. The rat kidneys accumulated more B12 during normal and loaded conditions than any other tissue. A 110-fold increase in vitamin content was observed from the deficient to the loaded conditions in the kidney compared with a 3.5-fold increase in the liver. In contrast to all other organs, significantly smaller amounts of acutely injected B12 accumulated in the kidneys in the vitamin-deprived state compared with both the normal and the vitamin-loaded condition. Conclusions. The present study suggests a significant role for the rodent kidney in vitamin B12 metabolism. We propose a model for rat tissue uptake consistent with the presence of two different TC-B12 receptors and renal uptake following filtration of TCB12 in the glomeruli. The presented model allows for the reduced renal uptake and accumulation in vitamindeprived conditions, thus reserving the vitamin for other tissues, including nerve tissue and bone marrow, which are more sensitive to vitamin B12 deficiency. Introduction Vitamin B12 acts as a cofactor in the production of succinyl-CoA and the essential amino acid methionine in the mitochondrial fraction and cytoplasm, respectively. Vitamin deficiency is associated with severe neurological and haematological symptoms, identifying the nervous tissue and the bone marrow as the organs most sensitive to vitamin deficiency. Because of the high vitamin B12 content in the human liver, this organ traditionally has been considered the major storage site for vitamin B12 [1]. However, a possible role for the rat kidney is suggested by the well known ability of this organ to accumulate the vitamin during states of vitamin surplus [24]. Absorbed B12 is transported to the tissues bound to transcobalamin (TC). Two receptors for the uptake of TCB12 have been reported in rats: (i) the multiligand, endocytic receptor megalin [4,5]; and (ii) a 62 kDa protein of as yet unknown structure [6,7]. Megalin (600 kDa) belongs to the low density lipoprotein (LDL) receptor family and is heavily expressed in kidney proximal tubules [8] and several other absorptive The term vitamin B12 is generally used for cyanocobalamin only. However, since the different forms of cobalamin may be converted into each other, the term vitamin B12 or B12 herein includes all forms of cobalamin identified by our assay, including also adenosylcobalamin, methylcobalamin and hydroxycobalamin. # 2003 European Renal AssociationEuropean Dialysis and Transplant Association epithelia (reviewed in [9]). Plasma TCB12 is filtered in the renal glomeruli and reabsorbed by megalin in the mouse proximal tubule [5]. Thus, significant amounts of vitamin B12 are reabsorbed from the ultrafiltrate by the kidney [4]. To evaluate the role of the kidney in vitamin B12 homeostasis, we have compared rat renal accumulation of vitamin B12 with other tissues, including brain, liver, testes, intestine, spleen and plasma, during states of vitamin B12 depletion and vitamin B12 load. Our data suggest a unique role for the rat kidney allowing for the reduced renal uptake and accumulation in vitamin-deprived conditions, thus reserving the vitamin for other tissues. The results support a model of tissue vitamin uptake consistent with the presence of two different TCB12 receptors in different tissues. Subjects and methods Animals Fifteen newly weaned, age-matched (4 weeks of age), male Wistar rats were divided into three groups: (i) vitamin B12depleted rats (ns5); (ii) normal rats (...truncated)


This is a preview of a remote PDF: https://ndt.oxfordjournals.org/content/18/6/1095.full.pdf

Henrik Birn, Ebba Nexø, Erik Ilsø Christensen, Rikke Nielsen. Diversity in rat tissue accumulation of vitamin B12 supports a distinct role for the kidney in vitamin B12 homeostasis, Nephrology Dialysis Transplantation, 2003, pp. 1095-1100, 18/6, DOI: 10.1093/ndt/gfg089