Glomerular Permeability to Protein Molecules – its Possible Structural Basis

Schneeberger, Eveline E.

doi:10.1159/000180366

Cited by 26 publications

(12 citation statements)

References 41 publications

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“…Previous studies (4,5,(12)(13)(14)(15)(16) demonstrate that both structures may be important for maintaining a stringent barrier for plasma proteins larger than 70 kDa. This study provides compelling evidence of the GESD and nephrin as the primary regulators of glomerular vascular permeability.…”

Section: Discussionmentioning

confidence: 97%

“…Tracer experiments with ferritin have suggested that the fenestrated endothelium with a potential pore size of 500 -1000-Å diameter is freely permeable to many large plasma proteins (3)(4)(5)(6)(7)(8)(9)(10)(11). Such studies have also implicated that the crucial barrier for plasma proteins larger than 70 kDa is maintained by the glomerular basement membrane (GBM) 1 and the glomerular epithelial slit diaphragms (GESD) (4,5,(12)(13)(14)(15)(16). The question as to which of these two substructures is important for normal glomerular permselectivity remains open.…”

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confidence: 99%

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Determinants of Vascular Permeability in the Kidney Glomerulus

Hamano¹,

Grunkemeyer²,

Sudhakar³

et al. 2002

Journal of Biological Chemistry

119

110

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The human kidneys filter 70 liters of blood plasma every day. The hallmark of almost all kidney diseases, whether acquired or genetic, is the leakage of plasma proteins into the urine because of alterations in the glomerular filtration unit of the kidney. In this regard, the human mutations in nephrin, podocin, ␣-actinin-4, COL4A3, and COL4A5 genes expressed in the glomeruli have been implicated to cause alterations in glomerular filtration apparatus. Nevertheless, the expression of these proteins in relation to each other in mouse models for glomerular vascular leak is unknown. Additionally, within the glomerulus, the central question of whether the primary filtration barrier is the basement membrane or the epithelial slit diaphragm remains ambiguous. Therefore, in this study, we examined the localization and expression of glomerular epithelial slit diaphragm and glomerular basement membrane proteins implicated in glomerular vascular leak using mice deficient in either the ␣3 chain of type IV collagen, the major constituent of glomerular basement membrane, or LMX1B transcription factor, which regulates the expression of key glomerular type IV collagen genes COL4A3 and COL4A4 or nephrin, a glomerular epithelial slit diaphragm-associated protein. This study demonstrates that decreased expression of slit diaphragm protein, nephrin, correlates with a loss of glomerular filter integrity. Additionally, we demonstrate that defects induced by proteins of glomerular basement membrane lead to an insidious plasma protein leak, whereas the defects induced by proteins in the glomerular epithelial slit diaphragms lead to a precipitous plasma protein leak.

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

Determinants of Vascular Permeability in the Kidney Glomerulus

Hamano¹,

Grunkemeyer²,

Sudhakar³

et al. 2002

Journal of Biological Chemistry

119

110

View full text Add to dashboard Cite

show abstract

“…This knowledge has been based largely on experiments using tracers which can be visualized at the ultrastructural level (28,29). The early studies of Farquhar et al (6), showed that the lamina densa of the GBM behaved as a filtration barrier for large protein molecules, such as ferrifin; later studies using peroxidatic enzymes of mol wt ranging from 12,000-240,000 indicated that a second filtration barrier resides in the slit pore complex (7,9,10,28).…”

Section: Current Concepts Of Normal Glomerular Filtrationmentioning

confidence: 99%

Altered Functional Properties of the Renal Glomerulus in Autologous Immune Complex Nephritis

Schneeberger

Leber

Karnovsky

et al. 1974

The Journal of Experimental Medicine

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The present study was undertaken in order to investigate the nature of the glomerular damage in a form of experimental immune complex nephritis. The model of autologous immune complex nephritis (AIC) 1 (Heymann's nephritis) (1) was chosen for several reasons. First, the model bears a remarkable resemblance, in terms of ultrastructural and immunofluorescence features, to an important renal disease in man, membranous glomerulonephritis. Furthermore, the model is highly reproducible. In addition, the basic pathogenetic mechanism has been thoroughly documented (2-4). Briefly, the disease is produced in rats by immunization with homologous kidney preparations, which results in the formation of autoantibodies against a renal antigen, normally found in the brush border of proximal tubules. This antigen is presumed to enter the circulation in small amounts and combine with autoantibody to form complexes which deposit in glomeruli. 2 The complexes are detected as granular deposits of immunoglobulin and complement along the epithelial side of the glomerular basement membrane. The disease, like its human counterpart, is manifested by proteinuria, which is often heavy.Our approach was to use the enzymatic tracers horseradish peroxidase (HRP) (40,000 daltons) and catalase (240,000 daltons), and the electronopaque tracer ferritin (ca. 500,000 daltons) as probe molecules with which to assess the altered functional properties of the glomerular capillary wall. These ultrastructural tracers can be directly visualized, and their location within the glomerular capillary wall can be followed at sequential intervals after intravenous injection. Such protein tracers have been extensively used to identify * This study was supported by U.S. Public Health Service grants no. AM 16392 and AM 13132.1Abbreviations used in this paper: AIC, autologous immune complex; CFA, complete Freund's adjuvant; CL, capillary lumen; DAB, 3,3' diaminobenzidine-tetra-HC1; GBM, glomerniar basement membrane; HRP, horseradish peroxidase; US, urinary space.It is of interest that a related pathogenetic mechanism may operate in man. It has recently been reported that a tubular-derived antigen may be present in the glomerular immune deposits in some cases of human membranous glomerulonephritis (5).

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“…Recent studies of the glomerular capillary wall suggest an additional barrier to the passage of plasma proteins, at least to those of molecular size of albumin and larger. This barrier appears to be at the slit pore between the foot processes of the visceral epithelial cells [14,28,32].…”

mentioning

confidence: 99%

Value of the Sieving Coefficient in the Interpretation of Renal Protein Clearances

Pollak¹,

First²,

Pesce³

1974

Nephron

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The techniques of differential protein clearance have been used in the study of patients with renal disease in an attempt to predict the nature of the underlying renal abnormality. Many assumptions that underlie their use are subject to doubt, and differential protein clearances appear to predict the nature of the glomerular disease only in patients with nephrotic syndrome and minimal glomerular changes. When the protein clearance is expressed in terms of the glomerular filtration rate (sieving coefficient), it is a useful index to differentiate the proteinurias associated with glomerular or with tubular damage. This physiologic measure can be used as a valid means of expressing protein handling by normal and diseased kidney.

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Glomerular Permeability to Protein Molecules – its Possible Structural Basis

Cited by 26 publications

References 41 publications

Determinants of Vascular Permeability in the Kidney Glomerulus

Determinants of Vascular Permeability in the Kidney Glomerulus

Altered Functional Properties of the Renal Glomerulus in Autologous Immune Complex Nephritis

Value of the Sieving Coefficient in the Interpretation of Renal Protein Clearances

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