Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications

Abstract

For nearly fifty years the proximal tubule has been known to reabsorb, process, and either catabolize or transcytose albumin from the glomerular filtrate. Innovative techniques and approaches have provided insights into these processes, and several genetic diseases, nonselective proximal tubule cell (PTC) defects, chronic kidney disease and acute PTC injury lead to significant albuminuria, reaching nephrotic range. Albumin is also known to stimulate PTC injury cascades. Thus, the mechanisms of albumin reabsorption, catabolism and transcytosis are being reexamined utilizing techniques that allow for novel molecular and cellular discoveries. Megalin, a scavenger receptor, cubilin, amnionless, and Dab2 form a nonselective multi-receptor complex that mediates albumin binding, uptake and directs proteins for lysosomal degradation following endocytosis. The neonatal Fc receptor mediates albumin transcytosis by its pH-dependent binding affinity in endosomal compartments. This transcytotic, reclamation, pathway minimizes urinary losses and cellular catabolism of albumin thus prolonging its serum half-life. It also serves as a PTC molecular sorting mechanism to preserve and reclaim physiologic albumin while allowing "altered" albumin that does not bind to FcRn to enter the lysosomal pathway. The clinical importance of PTC albumin metabolism has also increased as albumin is now being used to bind therapeutic agents to extend their half-life and minimize filtration and kidney injury. The purpose of this review is to update and integrate evolving information regarding the reabsorption and processing of albumin by proximal tubule cells including discussing genetic disorders and therapeutic considerations.

New insights into proteinuria/albuminuria

“…The only studies that have done this is by Russo et al (Russo et al, 2009) and Sandoval et al (Sandoval et al, 2012) and accordingly they have obtained the relatively high GSCs for albumin. These GSC values have been confirmed by a body of work over the years (Wagner et al, 2016;Sandoval et al, 2019;Molitoris et al, 2022). These studies do provide what was originally expected when cell-mediated effects are not involved and knowing that charge selectivity is not a factor; the GSC of 36 Å radius Ficoll in healthy control humans = GSC of 36 Å radius Ficoll in nephrotic humans = the GSC of albumin in nephrotic humans = GSC of albumin in healthy controls (rats).…”

“…The only studies that have done this is by Russo et al ( Russo et al, 2009 ) and Sandoval et al ( Sandoval et al, 2012 ) and accordingly they have obtained the relatively high GSCs for albumin. These GSC values have been confirmed by a body of work over the years ( Wagner et al, 2016 ; Sandoval et al, 2019 ; Molitoris et al, 2022 ).…”

“…These models, however, have been extensively investigated and subsequently invalidated ( Comper and Russo, 2009 ; Comper, 2022 ). Other considerations have incorporated both glomerular filtration and tubular uptake ( Comper and Russo, 2009 ; Comper, 2014 ; Molitoris et al, 2022 ). This article reviews all these approaches contributing to proteinuria/albuminuria.…”

Increased severity of chronic kidney disease in response to high potassium intake is dependent on mineralocorticoid receptor activation

“…Proteinuria induces tubular lesions by several mechanisms. Endocytosis of albumin by the tubular cells is performed by the megalin/cubulin/amnionless pathway (28). Megalin acts in concert with PKB, stimulating cell survival.…”

Glycosylation of a key cubilin Asn residue results in reduced binding to albumin

“…Studies have documented both glomerular and proximal tubule (PT) alterations that can lead to albuminuria ( 5 ). Glomerular albumin filtration is accepted though levels of albumin filtration remain unresolved ( 6 ). Filtered albumin will arrive at the PT with associated ligands and various modifications depending upon physiologic state.…”