Renal Handling of Albumin-From Early Findings to Current Concepts

Abstract

Albumin is the main protein of blood plasma, lymph, cerebrospinal and interstitial fluid. The protein participates in a variety of important biological functions, such as maintenance of proper colloidal osmotic pressure, transport of important metabolites and antioxidant action. Synthesis of albumin takes place mainly in the liver, and its catabolism occurs mostly in vascular endothelium of muscle, skin and liver, as well as in the kidney tubular epithelium. Long-lasting investigation in this area has delineated the principal route of its catabolism involving glomerular filtration, tubular endocytic uptake via the multiligand scavenger receptor tandem-megalin and cubilin-amnionless complex, as well as lysosomal degradation to amino acids. However, the research of the last few decades indicates that also additional mechanisms may operate in this process to some extent. Direct uptake of albumin in glomerular podocytes via receptor for crystallizable region of immunoglobulins (neonatal FC receptor) was demonstrated. Additionally, luminal recycling of short peptides into the bloodstream and/or back into tubular lumen or transcytosis of whole molecules was suggested. The article discusses the molecular aspects of these processes and presents the major findings and controversies arising in the light of the research concerning the last decade. Their better characterization is essential for further research into pathophysiology of proteinuric renal failure and development of effective therapeutic strategies.

Keywords: albumin; cubilin; megalin; proteinuria; renal catabolism of proteins; renal proximal tubule.

Figure 1

Endocytic megalin-cubilin-amnionless complex in the apical membrane of the renal proximal tubule.

Figure 2

Renal catabolism of albumin—current concepts and alternatives. The generally accepted model assumes a relatively low level of glomerular albumin filtration due to its relatively large size and low isoelectric point, efficient reabsorption by endocytosis, involving megalin and cubilin-amnionless complex, vesicular transport to lysosomes and hydrolysis to single amino acid residues. In this model, only a negligible amount of albumin is excreted in urine, and the degradation products mostly return to circulation. The controversies concern both the quantitative and qualitative aspects of this process. New studies indicate, inter alia, that albumin permeation can occur with a GSC of 0.04. In the proposed model, native molecules undergo mainly transcytosis, while structurally modified molecules, i.e., oxidized or glycated, follow the classical path, with lysosomal degradation taking place to a limited extent. Most degradation products are short polypeptides that are secreted into the lumen of the tubule.