The proximal tubule and albuminuria: really!

Abstract

Recent data highlight the role of the proximal tubule (PT) in reabsorbing, processing, and transcytosing urinary albumin from the glomerular filtrate. Innovative techniques and approaches have provided exciting insights into these processes, and numerous investigators have shown that selective PT cell defects lead to significant albuminuria, even reaching nephrotic range in animal models. Thus, the mechanisms of albumin reabsorption and transcytosis are undergoing intense study. Working in concert with megalin and cubilin, a nonselective multireceptor complex that predominantly directs proteins for lysosomal degradation, the neonatal Fc receptor (FcRn) located at the brush border of the apical membrane has been implicated as the "receptor" mediating albumin transcytosis. The FcRn pathway facilitates reabsorption and mediates transcytosis by its pH-dependent binding affinity in endosomal compartments. This also allows for selective albumin sorting within the PT cell. This reclamation pathway minimizes urinary losses and catabolism of albumin, thus prolonging its serum half-life. It may also serve as a molecular sorter to preserve and reclaim normal albumin while allowing "altered" albumin to be catabolized via lysosomal pathways. Here, we critically review the data supporting this novel mechanism.

Keywords: FcRn; cubulin; endocytosis; megalin; nephrotic syndrome; transcytosis.

Figure 1.

Albumin filtration across the glomerulus is greater than previously thought and reclaimed by the PTC, especially S1 cells. (A) Albumin filtered at the level of the glomerular capillaries into the Bowman space is taken up after binding by the megalin-cubilin receptor complex or perhaps by the FcRn lining the brush border of proximal tubular cells. Albumin is internalized to PTCs by receptor-mediated endocytosis via clathrin-coated vesicles and fluid-phase endocytosis. From there it can be catabolized via lysosomal degradation or can be transcytosed. Albumin fragments in the urinary lumen result from lysosomal exocytosis or peptide hydrolysis by apical membrane proteases. (B) In vivo image of 25-micron three-dimensional volume showing amounts of Texas red–labeled albumin uptake into PTCs (arrow), especially the S-1 segment (S1). G, glomerular capillaries. Bar=20 µm.

Figure 2.

FcRn mediates pH-dependent transcytosis and intracellular sorting of reabsorbed albumin. Albumin is reabsorbed via both receptor-mediated clathrin-coated pits into vesicles (CCV) (1a) and by fluid-phase (clathrin-negative) endocytosis (1b). Following endocytosis, endosomal acidification occurs (2), causing dissociation of albumin from receptors, such as megalin-cubilin complexes. However, acidification enhances albumin binding to FcRn throughout endocytic compartments; thus, there is exchange of albumin from the megalin-cubulin complex to FcRn. Within the endosomal-sorting compartment (ESC), albumin is directed toward lysosomal degradation or the transcytotic pathway (3). Transcytosis occurs by both vascular and tubular structures mediating albumin delivery to the basolateral membrane (4). Upon fusion with the basolateral membrane, the increase in pH of the extracellular environment causes dissociation of albumin from FcRn; FcRn is then recycled back to the apical membrane via the recycling compartment. It is possible that albumin’s binding to FcRn is reduced by alterations, such as glycosylation and carbamylation; thus, transcytosis of albumin would not occur and albumin would enter the lysosomal pathway. This would provide an intracellular molecular sorting mechanism to preserve physiologic albumin and facilitate catabolism of chemically altered albumin. FPV, fluid-phase vesicle; L, lysosome; RC, recycling compartment; TJ, tight junction.