Desulphation of dextran sulphate during kidney ultrafiltration

Comper, Wayne D.; M, Tay; Wells, X; Dawes, J.

doi:10.1042/bj2970031

Cited by 41 publications

(25 citation statements)

References 16 publications

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“…Opposing that coherent body of theory and experiment are other data suggesting that some of the apparent charge selectivity may be artifactual, due to cellular processing of charged solutes (7). More recent papers demonstrate both enhanced transport of anionic tracers compared with neutral ones and in vivo studies in which reducing the charge of the basement membrane gel had negligible effect on permselectivity to albumin (3,6,20,22,35).…”

Section: Discussionmentioning

confidence: 96%

“…In parallel with ultrastructural studies mapping solute distributions in the capillary wall, seminal studies by Brenner and Deen using inert tracers suggested that glomerular transport of negatively charged solutes was much lower than that of comparably sized neutral solutes (5,23,33,34). Subsequent work by Comper and colleagues (7,38) attributed the measured difference in urine concentrations of neutral and sulfated dextrans to desulfation of the dextran during its passage across the capillary wall. Multiple investigators have published studies comparing charged and neutral proteins consistent with a glomerular charge barrier (4,30).…”

mentioning

confidence: 94%

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Molecular conformation and filtration properties of anionic Ficoll

Groszek

Ferrell

et al. 2010

American Journal of Physiology-Renal Physiology

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The physiology of glomerular permselectivity remains mechanistically obscure, despite its importance in human disease. Although electrical contributions to glomerular permselectivity have long been considered important, two recent reports demonstrated enhanced glomerular permeability to anionic versus neutral polysaccharides. The interpretation of these observations is complicated by confounding of the effects of chemical modification on charge with effects on size and shape. In this report, neutral and anionic Ficoll are characterized by size-exclusion chromatography with online light scattering and viscometry and filtration through a highly defined anionic filtration membrane. Neutral and carboxymethylated Ficoll are nearly identical in size and conformation, yet carboxymethylated Ficoll is retained by an anionic membrane in excess of neutral Ficoll. This suggests that comparisons between clearances of neutral and carboxymethylated Ficoll may be a sensitive probe of electrostatic interactions independent of size and conformation.

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 94%

Molecular conformation and filtration properties of anionic Ficoll

Groszek

Ferrell

et al. 2010

American Journal of Physiology-Renal Physiology

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show abstract

“…However, this proved to be an erroneous conclusion because it was later demonstrated that the apparent charge selectivity could be destroyed by merely increasing the concentration of circulating dextran sulfate [13]. This was related to the fi nding that dextran sulfate was not an inert transport probe [14] but was desulfated by endothelial cells [15]. The process was saturable because at higher concentrations there was no desulfation and no apparent charge selectivity [13].…”

Section: Gsc Of Negatively Charged Transport Probesmentioning

confidence: 94%

Where does albuminuria come from in diabetic kidney disease?

Comper

Russo²

2008

Curr Diab Rep

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The classic mechanism to explain albumin excretion in diabetes has been permeability defects in the glomerular fi lter. However, a new concept has emerged that albuminuria can be explained by the two major pathways the proximal tubular cell uses to process fi ltered albumin. Specifi cally, albumin permeability through the glomerular fi lter is only governed by size selectivity. Most of the fi ltered albumin is retrieved by the proximal tubular cell and returned to the peritubular blood supply. Albuminuria in the nephrotic range would arise from retrieval pathway dysfunction. The small quantities of fi ltered albumin that are not retrieved undergo obligatory lysosomal degradation before urinary excretion as small peptide fragments. This pathway is sensitive to metabolic factors responsible for hypertrophy and fi brosis, particularly molecules such as angiotensin II and transforming growth factor-β1, whose production is stimulated by hyperglycemic environments. Dysfunction in this degradation pathway may lead to albuminuria below the nephrotic range.

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“…Subsequently it was demonstrated that dextran sulfate is desulfated during filtration in vivo (27) and that this cell-mediated desulfation process is responsible for the apparent differences in glomerular sieving of dextran sulfate compared with uncharged dextran (16,124). Dextran sulfate itself does not bind to albumin (16) under physiological conditions, and therefore this does not contribute to apparent differences in transglomerular transport.…”

Section: Charge Selectivity Cannot Account For the Low Glomerular Permentioning

confidence: 98%

Disease-dependent mechanisms of albuminuria

Comper

Hilliard²,

Nikolic‐Paterson

et al. 2008

American Journal of Physiology-Renal Physiology

138

116

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The mechanism of albuminuria is perhaps one of the most complex yet important questions in renal physiology today. Recent studies have directly demonstrated that the normal glomerulus filters substantial amounts of albumin and that charge selectivity plays little or no role in preventing this process. This filtered albumin is then processed by proximal tubular cells by two distinct pathways; dysfunction in either one of these pathways gives rise to discrete forms of albuminuria. Most of the filtered albumin is returned to the peritubular blood supply by a retrieval pathway. Albuminuria in the nephrotic range would arise from retrieval pathway dysfunction. The small quantities of filtered albumin that are not retrieved undergo obligatory lysosomal degradation before urinary excretion as small peptide fragments. This degradation pathway is sensitive to metabolic factors responsible for hypertrophy and fibrosis, particularly molecules such as angiotensin II and transforming growth factor-beta1, whose production is stimulated by hyperglycemic and hypertensive environments. Dysfunction in this degradation pathway leads to albuminuria below the nephrotic range. These new insights into albumin filtration and processing argue for a reassessment of the role of podocytes and the slit diaphragm as major direct determinants governing albuminuria, provide information on how glomerular morphology and "tubular" albuminuria may be interrelated, and offer a new rationale for drug development.

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Desulphation of dextran sulphate during kidney ultrafiltration

Cited by 41 publications

References 16 publications

Molecular conformation and filtration properties of anionic Ficoll

Molecular conformation and filtration properties of anionic Ficoll

Where does albuminuria come from in diabetic kidney disease?

Disease-dependent mechanisms of albuminuria

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