Recombinant Activated Factor VII Is Reabsorbed in Renal Proximal Tubules and Is a Ligand to Megalin and Cubilin.
Summary of "Recombinant Activated Factor VII Is Reabsorbed in Renal Proximal Tubules and Is a Ligand to Megalin and Cubilin."
Background/Aims: Recombinant activated factor VIIa (rFVIIa) is used for treatment of haemophilia patients with inhibitors. Tissue distribution studies in rats have shown that injected (125)I-rFVIIa accumulates in organs such as the liver and the kidneys. In this study, we explored which mechanism could be involved in renal clearance of rFVIIa. Methods: Immunohistochemistry was used for examination of the renal distribution in detail after injection of rFVIIa to mice and rats. Surface plasmon resonance evaluated specific binding of rFVIIa to megalin and cubilin. The biological function of megalin and cubilin in rFVIIa endocytosis was explored in opossum kidney (OK) cells. Results: Staining of rFVIIa was observed only in endosomes and lysosomes within proximal convoluted tubules from renal cortex of mice and rats. Specific binding of rFVIIa to megalin and cubilin was in the presence of receptor-associated protein (RAP) obliterated and reduced by approximately 50%, respectively. Immunofluorescence microscopy and a quantitative cellular endocytosis showed uptake in OK cells of either rFVIIa or (125)I-rFVIIa, and this uptake was significantly decreased in the presence of RAP. Conclusion: We suggest that the renal cortex plays a significant role in clearance of injected rFVIIa and that endocytosis and degradation of rFVIIa in proximal tubule cells is mediated via binding to megalin and cubilin.
Affiliation
Exploratory ADME, Biopharmaceuticals, Novo Nordisk A/S, Måløv, Denmark.
Journal Details
This article was published in the following journal.
Name: Nephron. Experimental nephrology
ISSN: 1660-2129
Pages: e82-e92
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20861656
- DOI: http://dx.doi.org/10.1159/000321161
Medical and Biotech [MESH] Definitions
Acidosis, Renal Tubular
A group of genetic disorders of the KIDNEY TUBULES characterized by the accumulation of metabolically produced acids with elevated plasma chloride, hyperchloremic metabolic ACIDOSIS. Defective renal acidification of URINE (proximal tubules) or low renal acid excretion (distal tubules) can lead to complications such as HYPOKALEMIA, hypercalcinuria with NEPHROLITHIASIS and NEPHROCALCINOSIS, and RICKETS.
Kidney Tubules, Proximal
The renal tubule portion that extends from the BOWMAN CAPSULE in the KIDNEY CORTEX into the KIDNEY MEDULLA. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the U-shaped LOOP OF HENLE.
Glycosuria, Renal
An autosomal inherited disorder due to defective reabsorption of GLUCOSE by the PROXIMAL RENAL TUBULES. The urinary loss of glucose can reach beyond 50 g/day. It is attributed to the mutations in the SODIUM-GLUCOSE TRANSPORTER 2 encoded by the SLC5A2 gene.
Renal Aminoacidurias
A group of inherited kidney disorders characterized by the abnormally elevated levels of AMINO ACIDS in URINE. Genetic mutations of transport proteins result in the defective reabsorption of free amino acids at the PROXIMAL RENAL TUBULES. Renal aminoaciduria are classified by the specific amino acid or acids involved.
Kidney Tubules
Long convoluted tubules in the nephrons. They collect filtrate from blood passing through the KIDNEY GLOMERULUS and process this filtrate into URINE. Each renal tubule consists of a BOWMAN CAPSULE; PROXIMAL KIDNEY TUBULE; LOOP OF HENLE; DISTAL KIDNEY TUBULE; and KIDNEY COLLECTING DUCT leading to the central cavity of the kidney (KIDNEY PELVIS) that connects to the URETER.
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