Retention of Albumin in the Circulation is Governed by Saturable Renal Cell‐Mediated Processes

Koltun, Maria; Comper, Wayne D.

doi:10.1080/10739680490437513

Cited by 24 publications

(25 citation statements)

References 34 publications

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“…[26][27][28] Finally, a study in Wistar rats using three albumin injections, versus two as in our study, showed no change in the glomerular size selectivity. 29 For the present study, we chose an acute albumin overload model using two albumin injections in normal healthy animals. In this model serum protein levels were maintained, but not increased.…”

Section: Discussionmentioning

confidence: 99%

Proximal Tubules Have the Capacity to Regulate Uptake of Albumin

Wagner

Campos-Bilderback

Chowdhury

et al. 2016

Journal of the American Society of Nephrology

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Evidence from multiple studies supports the concept that both glomerular filtration and proximal tubule (PT) reclamation affect urinary albumin excretion rate. To better understand these roles of glomerular filtration and PT uptake, we investigated these processes in two distinct animal models. In a rat model of acute exogenous albumin overload, we quantified glomerular sieving coefficients (GSC) and PT uptake of Texas Red-labeled rat serum albumin using two-photon intravital microscopy. No change in GSC was observed, but a significant decrease in PT albumin uptake was quantified. In a second model, loss of endogenous albumin was induced in rats by podocyte-specific transgenic expression of diphtheria toxin receptor. In these albumin-deficient rats, exposure to diphtheria toxin induced an increase in albumin GSC and albumin filtration, resulting in increased exposure of the PTs to endogenous albumin. In this case, PT albumin reabsorption was markedly increased. Analysis of known albumin receptors and assessment of cortical protein expression in the albumin overload model, conducted to identify potential proteins and pathways affected by acute protein overload, revealed changes in the expression levels of calreticulin, disabled homolog 2, NRF2, angiopoietin-2, and proteins involved in ATP synthesis. Taken together, these results suggest that a regulated PT cell albumin uptake system can respond rapidly to different physiologic conditions to minimize alterations in serum albumin level. 27: 482-494, 201627: 482-494, . doi: 10.1681 While the clinical relevance of proteinuria, and especially albuminuria, has been well documented, the quantitative and mechanistic significance of different components to albumin excretion remains an area of considerable excitement and debate. 1 Recent data from several laboratories utilizing different approaches have delineated a role of proximal tubules (PTs) in regulation of albumin reabsorption and reclamation. 2 Furthermore, albumin transcytosis has been visualized in PT cells 3 and FcRn has been shown to mediate the transcytosis of albumin across PTCs, 4 as it is known to do for many other cell types. 2 Therefore, the present studies were conducted to begin differentiating and quantifying glomerular and PT contributions to albuminuria under physiologic and disease conditions. This understanding is important because before appropriate therapies can be developed to modulate albuminuria, the structural, functional and mechanistic characterization need to be better understood and interrelated. J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 99%

Proximal Tubules Have the Capacity to Regulate Uptake of Albumin

Wagner

Campos-Bilderback

Chowdhury

et al. 2016

Journal of the American Society of Nephrology

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“…These local processes may hamper oxygen supply to adjacent tubular cells, known to be extremely vulnerable to oxygen deprivation. Furthermore, a tubular disbalance in energy expenditure and availability might also result in tubular ischemia, because tubular protein overloading leads to an increased lysosomal processing (13), affecting oxygen demand.…”

Section: Discussionmentioning

confidence: 99%

Tubular kidney injury molecule-1 in protein-overload nephropathy

Timmeren¹,

Bakker²,

Vaidya³

et al. 2006

American Journal of Physiology-Renal Physiology

164

108

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Kim-1, a recently discovered membrane protein, is undetectable in normal kidneys but markedly induced in proximal tubules after ischemic and toxic injury. The function of Kim-1 is unclear, but it is implicated in damage/repair processes. The Kim-1 ectodomain is cleaved by metalloproteinases and detectable in urine. We studied Kim-1 in a nontoxic, nonischemic, model of tubulointerstitial damage caused by acute proteinuria. Uninephrectomized (NX) rats received daily (ip) injections of 2 g BSA (NX+BSA, n = 12) or saline (NX, n = 6) for 3 wk. Kidneys were stained for various damage markers by immunohistochemistry (IHC). Kim-1 mRNA (RT-PCR, in situ hybridization), protein (IHC, Western blotting), and urinary Kim-1 (Luminex) were determined. Spatial relations between Kim-1 and other damage markers were studied by double labeling IHC. NX+BSA rats developed massive proteinuria (1,217 ± 313 vs. 18 ± 2 mg/day in NX, P < 0.001) and significant renal damage. Kim-1 mRNA was upregulated eightfold in NX+BSA (ratio Kim-1/β-actin, 4.08 ± 2.56 vs. 0.52 ± 0.64 in NX, P < 0.001) and localized to damaged tubules. Kim-1 protein expression was markedly induced in NX+BSA (2.46 ± 1.19 vs. 0.39 ± 0.10% staining/field in NX, P < 0.001). Urinary Kim-1 was significantly elevated in NX+BSA (921 ± 592 vs. 87 ± 164 pg/ml in NX, P < 0.001) and correlated with tissue Kim-1 expression ( r = 0.66, P =0.02). Kim-1 protein was found at the apical membrane of dilated nephrons. Kim-1 expression was limited to areas with inflammation (MØ), fibrosis (α-smooth muscle actin), and tubular damage (osteopontin), and only occasionally with tubular dedifferentiation (vimentin). These results implicate involvement of Kim-1 in the pathogenesis of proteinuria-induced renal damage/repair. Urinary Kim-1 levels may serve as a marker of proteinuria-induced renal damage.

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“…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. The equilibrium dissociation constant, K d , is much weaker at a pH of 7.0 (34-408 mM) versus a pH of 5.0 (0.2-0.7 mM).…”

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

233

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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Retention of Albumin in the Circulation is Governed by Saturable Renal Cell‐Mediated Processes

Cited by 24 publications

References 34 publications

Proximal Tubules Have the Capacity to Regulate Uptake of Albumin

Proximal Tubules Have the Capacity to Regulate Uptake of Albumin

Tubular kidney injury molecule-1 in protein-overload nephropathy

The Proximal Tubule and Albuminuria

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