Characterization of the urinary albumin degradation pathway in the isolated perfused rat kidney

Hilliard, Lucinda M; Osicka, Tanya M; Clavant, Steven P; Robinson, Phillip J.; Nikolic-Paterson, David J.; Comper, Wayne D.

doi:10.1016/j.lab.2005.08.008

Cited by 33 publications

(31 citation statements)

References 37 publications

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“…28 From the brush border of the PTEC, albumin can enter a high capacity transcytotic pathway 29 -32 or a lower capacity pathway directed toward lysosomal delivery and degradation. 17,[32][33][34] Our studies have confirmed and extended upon the studies of Anderson and colleagues relating to albumin metabolism in FcRn Ϫ/Ϫ mice, 12,23 with the t 1 ⁄2 for albumin in FcRn Ϫ/Ϫ mice 75% that of wild-type mice. The wild-type and FcRn Ϫ/Ϫ mice we studied were at steady state, with net production equaling that lost through metabolism.…”

Section: Discussionsupporting

confidence: 80%

“…Next, Sephacryl S-100 size-exclusion chromatography to separate urinary albumin was performed as described by the Comper laboratory. 17 This showed albumin appeared as a single intact peak in urines from both mouse strains ( Figure 1E). Albumin and IgG were also labeled with infrared dyes to allow direct visualization of their urinary forms after separation by SDS-PAGE.…”

Section: Clearance Of Albumin and Igg By Renal Fcrnmentioning

confidence: 89%

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Renal FcRn Reclaims Albumin but Facilitates Elimination of IgG

Sarav¹,

Wang²,

Hack³

et al. 2009

Journal of the American Society of Nephrology

113

115

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Section: Discussionsupporting

confidence: 80%

Section: Clearance Of Albumin and Igg By Renal Fcrnmentioning

confidence: 89%

Renal FcRn Reclaims Albumin but Facilitates Elimination of IgG

Sarav¹,

Wang²,

Hack³

et al. 2009

Journal of the American Society of Nephrology

113

115

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“…Overall, our data indicate that MiTMAB inhibits two mechanistically distinct forms of endocytosis via inhibition of dynamin I or dynamin II GTPase activity. The further potential for MiTMAB to block endocytosis in animals was recently demonstrated (Hilliard et al, 2006). Perfusion of exteriorized kidney with MiTMAB increased excretion of intact albumin.…”

Section: Discussionmentioning

confidence: 97%

Myristyl Trimethyl Ammonium Bromide and Octadecyl Trimethyl Ammonium Bromide Are Surface-Active Small Molecule Dynamin Inhibitors that Block Endocytosis Mediated by Dynamin I or Dynamin II

Quan

McGeachie²,

Keating³

et al. 2007

Mol Pharmacol

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112

141

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Dynamin is a GTPase enzyme involved in membrane constriction and fission during endocytosis. Phospholipid binding via its pleckstrin homology domain maximally stimulates dynamin activity. We developed a series of surface-active small-molecule inhibitors, such as myristyl trimethyl ammonium bromide (MiTMAB) and octadecyltrimethyl ammonium bromide (OcTMAB), and we now show MiTMAB targets the dynamin-phospholipid interaction. MiT-MAB inhibited dynamin GTPase activity, with a K i of 940 Ϯ 25 nM. It potently inhibited receptor-mediated endocytosis (RME) of transferrin or epidermal growth factor (EGF) in a range of cells without blocking EGF binding, receptor number, or autophosphorylation. RME inhibition was rapidly reversed after washout. The rank order of potency for a variety of MiTMAB analogs on RME matched the rank order for dynamin inhibition, suggesting dynamin recruitment to the membrane is a primary cellular target. MiTMAB also inhibited synaptic vesicle endocytosis in rat brain nerve terminals (synaptosomes) without inducing depolarization or morphological defects. Therefore, the drug rapidly and reversibly blocks multiple forms of endocytosis with no acute cellular damage. The unique mechanism of action of MiTMAB provides an important tool to better understand dynamin-mediated membrane trafficking events in a variety of cells.

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“…At the low pH found in endosomes, albumin dissociates from megalincubilin, while FcRn's affinity to bind both IgG and albumin increases dramatically. 90,91,100,115 Thus, albumin is capable of moving from a low-capacity lysosomal degradation pathway 39,116,117 to a high-capacity pathway of transcytosis and recycling mediated by FcRn based on inherent binding properties of the receptors. 39,[118][119][120] Binding studies have shown that FcRn has a single binding site for albumin that is distinct from the IgG site and that both these interactions are pH dependent.…”

Section: Role Of Fcrn In Ptc Albumin Processingmentioning

confidence: 99%

The Proximal Tubule and Albuminuria

Dickson

Wagner

Sandoval

et al. 2014

Journal of the American Society of Nephrology

232

227

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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. 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. DYSFUNCTIONAL PTCS LE...

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Characterization of the urinary albumin degradation pathway in the isolated perfused rat kidney

Cited by 33 publications

References 37 publications

Renal FcRn Reclaims Albumin but Facilitates Elimination of IgG

Renal FcRn Reclaims Albumin but Facilitates Elimination of IgG

Myristyl Trimethyl Ammonium Bromide and Octadecyl Trimethyl Ammonium Bromide Are Surface-Active Small Molecule Dynamin Inhibitors that Block Endocytosis Mediated by Dynamin I or Dynamin II

The Proximal Tubule and Albuminuria

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