Permselectivity of the glomerular capillary wall: III. Restricted transport of polyanions

Chang, Ramsay; Deen, William M.; Robertson, Channing R.; Brenner, Barry M.

doi:10.1038/ki.1975.104

Cited by 358 publications

(152 citation statements)

References 21 publications

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“…Since molecules with a molecular mass of 15-17 kDa are hindered only slightly in their passage across the capillary wall it follows that leptin with a molecular size of 16 kDa would be essentially freely filtered (Skorecki et al 1986). This conclusion must be tempered, however, by the fact that an acidic protein such as leptin bearing negative charges would be expected to show some restriction in its passage across the glomerular membrane (Chang et al 1975, Zhang et al 1994.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of leptin removal from the circulation by the kidney

Cumin¹,

Baum²,

Levens³

1997

Journal of Endocrinology

106

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This study was performed to test the hypothesis that the kidneys play a primary role in the clearance of endogenous leptin from the circulation. Lean male Sprague-Dawley rats were anesthetized and subjected to various surgical manipulations of the kidneys. Sixty minutes after surgery arterial blood samples were taken at 1-h intervals for up to 8 h. Plasma leptin levels were determined by radioimmunoassay. Bilateral nephrectomy induced a rapid increase in plasma leptin concentrations above control values, indicating that the kidneys are important for the elimination of leptin from the circulation. Leptin was not metabolized across the renal circulation and was extracted intact by the kidney. Simultaneous measurement of renal plasma flow established renal leptin extraction at approximately 6·5 ng/min for both kidneys. Compared with the quantities extracted from the plasma, leptin was only present in the urine in small quantities, indicating extensive metabolic degradation in the renal tubules. High plasma leptin levels were not maintained after binephrectomy indicating that pathways other than the kidneys are also responsible for leptin clearance. Seven hours after bilateral ureteral ligation, a procedure which lowers glomerular filtration, plasma leptin levels were slightly elevated. The renal extraction of leptin did not change over a wide range of plasma leptin concentrations suggesting that renal leptin extraction is a high capacity, non-saturable process most probably glomerular filtration. Endogenous leptin is rapidly cleared from the circulation by glomerular filtration followed by metabolic degradation in the renal tubules.

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Section: Discussionmentioning

confidence: 99%

Mechanism of leptin removal from the circulation by the kidney

Cumin¹,

Baum²,

Levens³

1997

Journal of Endocrinology

106

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“…The concept of charge selectivity emerged from a series of now classic studies examining the clearance of tracers differing in charge. [1][2][3] The permeability of anionic tracers was lower than their neutral counterparts, whereas that of cationic forms was enhanced. It was concluded that an intrinsic or "fixed" negative charge in the capillary wall poses an electrostatic barrier to anionic plasma proteins, such as albumin.…”

mentioning

confidence: 99%

Disruption of Glomerular Basement Membrane Charge through Podocyte-Specific Mutation of Agrin Does Not Alter Glomerular Permselectivity

Harvey

Jarad

Cunningham

et al. 2007

The American Journal of Pathology

156

127

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Glomerular charge selectivity has been attributed to anionic heparan sulfate proteoglycans (HSPGs) in the glomerular basement membrane (GBM). Agrin is the predominant GBM-HSPG, but evidence that it contributes to the charge barrier is lacking, because newborn agrin-deficient mice die from neuromuscular defects. To study agrin in adult kidney, a new conditional allele was used to generate podocyte-specific knockouts. Mutants were viable and displayed no renal histopathology up to 9 months of age. Perlecan, a HSPG normally confined to the mesangium in mature glomeruli, did not appear in the mutant GBM, which lacked heparan sulfate. Moreover, GBM agrin was found to be derived primarily from podocytes. Polyethyleneimine labeling of fetal kidneys revealed anionic sites along both laminae rarae of the GBM that became most prominent along the subepithelial aspect at maturity; labeling was greatly reduced along the subepithelial aspect in agrin-deficient and conditional knockout mice. Despite this severe charge disruption, the glomerular filtration barrier was not compromised, even when challenged with bovine serum albumin overload. We conclude that agrin is not required for establishment or maintenance of GBM architecture. Although agrin contributes significantly to the anionic charge to the GBM, both it and its charge are not needed for glomerular permselectivity. This calls into question whether charge selectivity is a

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“…Alterations in the size and charge-dependent selectivity of the glomerular basement membrane (GBM) have been described in models of proteinuria (1)(2)(3)(4). Heparan sulfate proteoglycans (HSPG) that comprise a protein core covalently linked to glycosaminoglycan side chains, such as heparan sulfate (HS), are one of the most important constituents of the GBM (5).…”

mentioning

confidence: 99%

A Synthetic Heparanase Inhibitor Reduces Proteinuria in Passive Heymann Nephritis

Levidiotis

Freeman

Punler³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. The ␤-D-endoglycosidase heparanase has been proposed to be important in the pathogenesis of proteinuria by acting to selectively degrade the negatively charged side chains of heparan sulfate proteoglycans (HSPG) within the glomerular basement membrane (GBM). A loss of the negatively charged HSPG may result in alteration of the permselective properties of the GBM, loss of glomerular epithelial and endothelial cell anchor points, and liberation of growth factors. This study examined the effect of PI-88, a sulfated oligosaccharide heparanase inhibitor, on renal function, glomerular ultrastructure, and proteinuria. Continuous PI-88 infusion at 25 mg/kg per d did not adversely affect animal behavior, growth, or GFR. Cortical tubular vacuolation, however, was observed by light microscopy, and GBM thickness was significantly reduced in these animals (P Ͻ 0.0002). Tissue distribution studies using [35 S]-labeled PI-88 revealed high levels of radioactivity in the kidney after a single subcutaneous injection of 25 mg/kg, suggesting protracted accumulation; moreover, active PI-88 was detected in urine. In passive Heymann nephritis, PI-88 delivered as a continuous infusion at 25 mg/kg per d significantly reduced autologous-phase proteinuria, at day 14 (P Ͻ 0.009), in the absence of altered sheep antibody deposition, C5b-9 deposition, and circulating rat anti-sheep antibody titers. Glomerular vascular endothelial growth factor and fibroblast growth factor expression was unaffected by PI-88 administration. However, PI-88 administration significantly prevented glomerular HSPG loss as demonstrated by quantitative immunofluorescence studies (P Ͻ 0.0001) in the absence of altered agrin distribution. These data therefore confirm the importance of heparanase in the development of proteinuria.

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Permselectivity of the glomerular capillary wall: III. Restricted transport of polyanions

Cited by 358 publications

References 21 publications

Mechanism of leptin removal from the circulation by the kidney

Mechanism of leptin removal from the circulation by the kidney

Disruption of Glomerular Basement Membrane Charge through Podocyte-Specific Mutation of Agrin Does Not Alter Glomerular Permselectivity

A Synthetic Heparanase Inhibitor Reduces Proteinuria in Passive Heymann Nephritis

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