J Am Soc Nephrol 25(3): 443-453

The Proximal Tubule and Albuminuria: Really!

Indiana University School of Medicine, The Roudebush Veterans Affairs Medical Center, Indiana Center for Biological Microscopy, Indianapolis, Indiana

^{Corresponding author.}

Correspondence: Dr. Bruce A. Molitoris, Nephrology Division, Department of Medicine, Indiana University School of Medicine, 950 West Walnut Street, Building R2, Room 266, Indianapolis, IN 46202. Email: ude.iupui@rotilomb

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: endocytosis, transcytosis, nephrotic syndrome, FcRn, megalin, cubulin

Abstract

Although the importance of urinary albumin in disease progression is known, the key mechanisms mediating the presence and toxic effects of albuminuria remain to be determined. Recently, the quantitative role of the glomerular filtration barrier (GFB) and the proximal tubule (PT) cell (PTC) in the development of albuminuria has been reexamined. Different lines of evidence, from multiple investigative teams, now suggest that the filtration of albumin, under physiologic conditions, is greater than previously determined. These data suggest an increased clinical role for the PT in minimizing albuminuria through the reabsorption of albumin. Emerging data also suggest that both glomerular permeability and PTCs play fundamental, physiologic, synergistic, interactive, and dynamic roles in the renal handling of albumin. Furthermore, it appears that PTCs, especially in the S1 segment, have specific mechanisms for efficiently and effectively reabsorbing and transcytosing albumin (reclamation). Therefore, the purpose of this review is to describe the emerging data regarding PTC albumin handling and provide a framework for considering future exciting, insightful, and novel studies with direct clinical relevance.

This review is not intended to debate the important role of the GFB but to emphasize that the PT should be considered important both under physiologic and pathologic conditions. We believe that glomerular or PTC defects can and do result in proteinuria. Specifically, we outline current data supporting PT uptake of albumin and mechanisms of reabsorption and transcytosis, and we propose a mechanism for intracellular sorting between degradation and transcytotic pathways based on pH-dependent binding.

Multiple PTC defects have been shown to lead to significant albuminuria. Notably, selective PTC injury using dophtheria toxin induction, essentially eliminating any PT uptake of albumin, resulted in severe, but reversible, albuminuria without histologic or electron microscopic changes.

Acknowledgments

The authors acknowledge grant support to B.A.M. from the National Institutes of Health (DK 091623 and 079312) and support from the Veterans Administration through a Merit Review award.

Acknowledgments

Footnotes

Published online ahead of print. Publication date available at www.jasn.org.

Footnotes

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