scholarly journals Glomerular permeability is not affected by heparan sulfate glycosaminoglycan deficiency in zebrafish embryos

2019 ◽  
Vol 317 (5) ◽  
pp. F1211-F1216 ◽  
Author(s):  
Ramzi Khalil ◽  
Reshma A. Lalai ◽  
Malgorzata I. Wiweger ◽  
Cristina M. Avramut ◽  
Abraham J. Koster ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Heparan Sulfate ◽  
Glomerular Filtration ◽  
Glomerular Basement Membrane ◽  
Experimental Models ◽  
Tubular Reabsorption ◽  
Glomerular Filtration Barrier ◽  
Glomerular Permeability ◽  
Tracer Injection ◽  
Filtration Barrier

Proteinuria develops when specific components in the glomerular filtration barrier have impaired function. Although the precise components involved in maintaining this barrier have not been fully identified, heparan sulfate proteoglycans are believed to play an essential role in maintaining glomerular filtration. Although in situ studies have shown that a loss of heparan sulfate glycosaminoglycans increases the permeability of the glomerular filtration barrier, recent studies using experimental models have shown that podocyte-specific deletion of heparan sulfate glycosaminoglycan assembly does not lead to proteinuria. However, tubular reabsorption of leaked proteins might have masked an increase in glomerular permeability in these models. Furthermore, not only podocytes but also glomerular endothelial cells are involved in heparan sulfate synthesis in the glomerular filtration barrier. Therefore, we investigated the effect of a global heparan sulfate glycosaminoglycan deficiency on glomerular permeability. We used a zebrafish embryo model carrying a homozygous germline mutation in the ext2 gene. Glomerular permeability was assessed with a quantitative dextran tracer injection method. In this model, we accounted for tubular reabsorption. Loss of anionic sites in the glomerular basement membrane was measured using polyethyleneimine staining. Although mutant animals had significantly fewer negatively charged areas in the glomerular basement membrane, glomerular permeability was unaffected. Moreover, heparan sulfate glycosaminoglycan-deficient embryos had morphologically intact podocyte foot processes. Glomerular filtration remains fully functional despite a global reduction of heparan sulfate.

scholarly journals Tensin2 is important for podocyte-glomerular basement membrane interaction and integrity of the glomerular filtration barrier

2020 ◽  
Vol 318 (6) ◽  
pp. F1520-F1530
Author(s):  
Kozue Uchio-Yamada ◽  
Keiko Yasuda ◽  
Yoko Monobe ◽  
Ken-ichi Akagi ◽  
Osamu Suzuki ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Glomerular Filtration ◽  
Glomerular Basement Membrane ◽  
Dependent Manner ◽  
Glomerular Filtration Barrier ◽  
Filtration Barrier ◽  
Gbm Thickening ◽  
Strain Dependent ◽  
Deficient Mice

Tensin2 (Tns2), an integrin-linked protein, is enriched in podocytes within the glomerulus. Previous studies have revealed that Tns2-deficient mice exhibit defects of the glomerular basement membrane (GBM) soon after birth in a strain-dependent manner. However, the mechanisms for the onset of defects caused by Tns2 deficiency remains unidentified. Here, we aimed to determine the role of Tns2 using newborn Tns2-deficient mice and murine primary podocytes. Ultrastructural analysis revealed that developing glomeruli during postnatal nephrogenesis exhibited abnormal GBM processing due to ectopic laminin-α2 accumulation followed by GBM thickening. In addition, analysis of primary podocytes revealed that Tns2 deficiency led to impaired podocyte-GBM interaction and massive expression of laminin-α2 in podocytes. Our study suggests that weakened podocyte-GBM interaction due to Tns2 deficiency causes increased mechanical stress on podocytes by continuous daily filtration after birth, resulting in stressed podocytes ectopically producing laminin-α2, which interrupts GBM processing. We conclude that Tns2 plays important roles in the podocyte-GBM interaction and maintenance of the glomerular filtration barrier.

Glomerular Endothelium and its Impact on Glomerular Filtration Barrier in Diabetes: Are the Gaps Still Illusive?

2018 ◽  
Vol 25 (13) ◽  
pp. 1525-1529 ◽  
Author(s):  
Joseph Fomusi Ndisang
Keyword(s):  
Endothelial Cells ◽  
Basement Membrane ◽  
Glomerular Filtration ◽  
Glomerular Basement Membrane ◽  
Healthy Individuals ◽  
Kidney Dysfunction ◽  
Glomerular Filtration Barrier ◽  
Filtration Barrier ◽  
Glomerular Endothelial Cells ◽  
Fenestrated Endothelium

Background: Glomerular capillaries are lined with highly specialized fenestrated endothelium which are primarily responsible to regulate high flux filtration of fluid and small solutes. During filtration, plasma passes through the fenestrated endothelium and basement membrane before it reaches the slit diaphragm, a specialized type of intercellular junction that connects neighbouring podocytes. Methods: A PubMed search was done for recent articles on components of the glomerular filtration barrier such as glomerular endothelial cells, podocytes and glomerular basement membrane, and the effect of diabetes on these structures. Results and Conclusion: Generally, the onset of kidney dysfunction in many diabetic patients is characterized by albuminuria/proteinuria, a pathophysiological event triggered by several factors including; (i) endothelial activation and shading of glycocalyx, (ii) loss of endothelial cell function, (ii) re-uptake of albumin by podocyte through a scavenger receptors and (iv) rearrangement of podocyte cytoskeleton. Howeover, as podocyte effacement does not always lead to proteinuria, the dynamic interplay between all constituents of the glomerular filtration barrier including podocytes, endothelial cells and the basement membrane may be fundamental for the effective filtration in healthy individuals. Thus, a putative cross-talk amongst podocytes, endothelial cells and the basement membrane in the homeostasis of glomerular function is envisaged. Although, the exact nature of this cross-talk remains to be clearly elucidated, it is possible that the interaction between: (i) glomerular endothelial cells and podocytes, (ii) glomerular endothelial cells and glomerular basement membrane, (iii) podocytes and glomerular basement membrane, and (iv) the simultaneous interaction amongst the three components collectively underpin effective filtration in healthy individuals. A comprehensive understanding of these different interactions still remains elusive. The elucidation of these multifaceted interactions will set the stage for greater understanding of the pathophysiology of kidney dysfunction.

scholarly journals A new function for parietal epithelial cells: a second glomerular barrier

2009 ◽  
Vol 297 (6) ◽  
pp. F1566-F1574 ◽  
Author(s):  
Takamoto Ohse ◽  
Alice M. Chang ◽  
Jeffrey W. Pippin ◽  
George Jarad ◽  
Kelly L. Hudkins ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Basement Membrane ◽  
Glomerular Filtration ◽  
Glomerular Filtration Barrier ◽  
Impermeable Barrier ◽  
Filtration Barrier ◽  
Proximal Tubular ◽  
Parietal Epithelial Cells ◽  
Glomerular Barrier

The functional role of glomerular parietal epithelial cells (PECs) remains poorly understood. To test the hypothesis that PECs form an impermeable barrier to filtered protein through the formation of tight junctions (TJ), studies were performed in normal animals and in the anti-glomerular basement membrane (GBM) model of crescentic nephritis. Electron microscopy showed well-defined TJ between PECs in normal mice, which no longer could be identified when these cells became extensively damaged or detached from their underlying Bowman's basement membrane. The TJ proteins claudin-1, zonula occludens-1, and occludin stained positive in PECs; however, staining decreased in anti-GBM disease. To show that these events were associated with increased permeability across the PEC-Bowman's basement membrane barrier, control and diseased animals were injected intravenously with either Texas red-conjugated dextran (3 kDa) or ovalbumin (45 kDa) tracers. As expected, both tracers were readily filtered across the glomerular filtration barrier and taken up by proximal tubular cells. However, when the glomerular filtration barrier was injured in anti-GBM disease, tracers were taken up by podocytes and PECs. Moreover, tracers were also detected between PECs and the underlying Bowman's basement membrane, and in many instances were detected in the extraglomerular space. We propose that together with its underlying Bowman's basement membrane, the TJ of PECs serve as a second barrier to protein. When disturbed following PEC injury, the increase in permeability of this layer to filtered protein is a mechanism underlying periglomerular inflammation characteristic of anti-GBM disease.

scholarly journals Acute reactive oxygen species (ROS)-dependent effects of IL-1β, TNF-α, and IL-6 on the glomerular filtration barrier (GFB) in vivo

2015 ◽  
Vol 309 (9) ◽  
pp. F800-F806 ◽  
Author(s):  
Kristinn Sverrisson ◽  
Josefin Axelsson ◽  
Anna Rippe ◽  
Daniel Asgeirsson ◽  
Bengt Rippe
Keyword(s):  
Reactive Oxygen Species ◽  
Glomerular Filtration ◽  
Reactive Oxygen ◽  
Size Exclusion ◽  
Oxygen Species ◽  
Glomerular Filtration Barrier ◽  
Glomerular Permeability ◽  
Filtration Barrier ◽  
Tnf Α ◽  
Superoxide Scavenger

This study was performed to investigate the immediate actions of the proinflammatory cytokines IL-1β, TNF-α, and IL-6 on the permeability of the glomerular filtration barrier (GFB) in rats and to test whether these actions are dependent upon the release of reactive oxygen species (ROS). In anesthetized rats, blood access was achieved and the left ureter was cannulated for urine collection. Rats were continuously infused intravenously with either IL-1β (0.4 and 2 μg·kg−1·h−1), TNF-α (0.4 and 2 μg·kg−1·h−1), or IL-6 (4 and 8 μg·kg−1·h−1), together with polydisperse FITC-Ficoll-70/400 and inulin for 1 h. Plasma and urine samples were analyzed by high performance size exclusion chromatography (HPSEC) for determination of glomerular sieving coefficients (θ). The glomerular filtration rate (GFR) was also assessed (51Cr-EDTA). In separate experiments, the superoxide scavenger tempol (30 mg·kg−1·h−1) was given before and during cytokine infusions. IL-1β and TNF-α caused rapid, partly reversible increases in glomerular permeability to large molecules (Ficoll50–80Å), peaking at 5–30 min, while IL-6 caused a more gradual increase in permeability, leveling off at 60 min. Tempol almost completely abrogated the glomerular permeability effects of the cytokines infused. In conclusion IL-1β, TNF-α, and IL-6, when infused systemically, caused immediate and partly reversible increases in glomerular permeability, which could be inhibited by the superoxide scavenger tempol, suggesting an important role of ROS in acute cytokine-induced permeability changes in the GFB.

Reduced diffusion of charge-modified, conformationally intact anionic Ficoll relative to neutral Ficoll across the rat glomerular filtration barrier in vivo

2011 ◽  
Vol 301 (4) ◽  
pp. F708-F712 ◽  
Author(s):  
Josefin Axelsson ◽  
Kristinn Sverrisson ◽  
Anna Rippe ◽  
William Fissell ◽  
Bengt Rippe
Keyword(s):  
Glomerular Filtration ◽  
High Performance ◽  
Size Exclusion ◽  
Glomerular Filtration Barrier ◽  
Glomerular Permeability ◽  
Charge Effects ◽  
Filtration Barrier ◽  
A Charge

The glomerular filtration barrier (GFB) is commonly conceived as a negatively charged sieve to proteins. Recent studies, however, indicate that glomerular charge effects are small for anionic, carboxymethylated (CM) dextran vs. neutral dextran. Furthermore, two studies assessing the glomerular sieving coefficients (θ) for negative CM-Ficoll vs. native Ficoll have demonstrated an increased glomerular permeability for CM-Ficoll (Asgeirsson D, Venturoli D, Rippe B, Rippe C. Am J Physiol Renal Physiol 291: F1083–F1089, 2006; Guimarães M, Nikolovski J, Pratt L, Greive K, Comper W. Am Physiol Renal Physiol 285: F1118–F1124, 2003.). The CM-Ficoll used, however, showed a larger Stokes-Einstein radius ( ae) than neutral Ficoll, and it was proposed that the introduction of negative charges in the Ficoll molecule had made it more flexible and permeable. Recently, a negative FITC-labeled CM-Ficoll (CMI-Ficoll) was produced with a conformation identical to that of neutral FITC-Ficoll. Using these probes, we determined their θ:s in anesthetized Wistar rats (259 ± 2.5 g). After blood access had been achieved, the left ureter was cannulated for urine sampling. Either polysaccharide was infused (iv) together with a filtration marker, and urine and plasma were collected. Assessment of θ FITC-Ficoll was achieved by high-performance size-exclusion chromatography (HPSEC). CMI-Ficoll and native Ficoll had identical elugrams on the HPSEC. Diffusion of anionic Ficoll was significantly reduced compared with that of neutral Ficoll across the GFB for molecules of ae ∼20–35 Å, while there were no charge effects for Ficoll of ae = 35–80 Å. The data are consistent with a charge effect present in “small pores,” but not in “large pores,” of the GFB and mimicked those obtained for anionic membranes in vitro for the same probes.

OPN deficiency results in severe glomerulosclerosis in uninephrectomized mice

2013 ◽  
Vol 304 (12) ◽  
pp. F1458-F1470 ◽  
Author(s):  
Sandra Schordan ◽  
Olaf Grisk ◽  
Eric Schordan ◽  
Bärbel Miehe ◽  
Elisabeth Rumpel ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Glomerular Basement Membrane ◽  
Mechanical Load ◽  
Experimental Models ◽  
Salt Treatment ◽  
Ki 67 ◽  
Matrix Deposition ◽  
Filtration Barrier ◽  
Renal Ablation ◽  
Normal Urine

Osteopontin (OPN) expression has been reported to be elevated in experimental models of renal injury such as arterial hypertension or diabetic nephropathy finally leading to focal segmental glomerulosclerosis (FSGS). FSGS is characterized by glomerular matrix deposition and loss or damage of podocytes that represent the main constituents of the glomerular filtration barrier. To evaluate the role of OPN in the kidney we investigated WT and OPN knockout mice (OPN−/−) without treatment, after uninephrectomy (UNX), as well as after UNX and desoxycorticosterone acetate (DOCA)-salt treatment with respect to urine parameters, glomerular morphology, and expression of podocyte markers. OPN−/− mice showed normal urine parameters while a thickening of the glomerular basement membrane was evident. Intriguingly, following UNX, OPN−/− mice exhibited prominent FSGS, proteinuria, and glomerular matrix deposition. Electron microscopy revealed bulgings of the glomerular basement membrane and occasionally an effacement of podocytes. After UNX and DOCA-salt treatment, severe glomerular lesions as well as proteinuria and albuminuria were seen in WT and OPN−/− mice. Moreover, we found a reduction of specific markers such as Wilm's tumor-1, podocin, and synaptopodin in both experimental groups indicating a loss of podocytes. Podocyte damage was accompanied by increased number of Ki-67-positive cells in the parietal epithelium of Bowman's capsule. We conclude that OPN plays a crucial role in adaptation of podocytes following renal ablation and is renoprotective when glomerular mechanical load is increased.

scholarly journals Glomerular filtration is normal in the absence of both agrin and perlecan–heparan sulfate from the glomerular basement membrane

2009 ◽  
Vol 24 (7) ◽  
pp. 2044-2051 ◽  
Author(s):  
Seth Goldberg ◽  
Scott J. Harvey ◽  
Jeanette Cunningham ◽  
Karl Tryggvason ◽  
Jeffrey H. Miner
Keyword(s):  
Basement Membrane ◽  
Heparan Sulfate ◽  
Glomerular Filtration ◽  
Glomerular Basement Membrane

Loss of size selectivity of the glomerular filtration barrier in rats following laparotomy and muscle trauma

2009 ◽  
Vol 297 (3) ◽  
pp. F577-F582 ◽  
Author(s):  
Josefin Axelsson ◽  
Irma Mahmutovic ◽  
Anna Rippe ◽  
Bengt Rippe
Keyword(s):  
Glomerular Filtration ◽  
High Performance ◽  
Size Exclusion ◽  
Blunt Injury ◽  
Abdominal Muscles ◽  
Glomerular Filtration Barrier ◽  
Glomerular Permeability ◽  
Filtration Barrier ◽  
Muscle Trauma ◽  
Exclusion Chromatography

Posttraumatic microalbuminuria may be caused by either charge- or size-selective alterations in the glomerular filtration barrier, or both, and/or to a reduction in proximal tubular protein reabsorption. This study was performed to elucidate the pathophysiology of the increases in glomerular permeability occurring in rats exposed to a laparotomy or to a laparotomy and muscle trauma. In anesthetized Wistar rats (250–280 g), the left ureter was cannulated for urine collection, while simultaneously blood access was achieved. Rats were exposed to trauma by a laparotomy (L; n = 8), or by a combination of L and muscle trauma (MT; L+MT) induced by topical blunt injury of the abdominal muscles bilaterally. After L, muscles were crushed using hemostatic forceps at either 2 × 2 sites (“small” MT; n = 9), or at 2 × 5 sites (“large” MT; n = 9). Sham groups ( n = 16), not exposed to a laparotomy, were used as controls. The glomerular sieving coefficients (θ) to polydisperse FITC-Ficoll-70/400 (molecular radius 13–80 Å) were determined at 5 or 60 min after L and L+MT, respectively, from plasma and urine samples, and analyzed by high-performance size-exclusion chromatography. A tissue-uptake technique was used to assess θ for 125I-labeled serum albumin. L, with or without MT, increased θ for Ficoll55–80Å and albumin rapidly and markedly. θ-Ficoll70Å thus increased approximately threefold, and θ for albumin significantly, for all trauma groups. According to the “two-pore model” of glomerular permeability, these changes mainly reflect an increase in the number of large pores in the glomerular filter without any primary changes in the charge-selective properties of the filter.

scholarly journals The Glomerular Filtration Barrier: Components and Crosstalk

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Madhav C. Menon ◽  
Peter Y. Chuang ◽  
Cijiang John He
Keyword(s):  
Endothelial Cell ◽  
Basement Membrane ◽  
Glomerular Filtration ◽  
Specific Reference ◽  
Glomerular Filtration Barrier ◽  
Filtration Barrier ◽  
Kidney Disease Progression ◽  
Injury Models ◽  
Visceral Epithelial Cell ◽  
High Conductance

The glomerular filtration barrier is a highly specialized blood filtration interface that displays a high conductance to small and midsized solutes in plasma but retains relative impermeability to macromolecules. Its integrity is maintained by physicochemical and signalling interplay among its three core constituents—the glomerular endothelial cell, the basement membrane and visceral epithelial cell (podocyte). Understanding the pathomechanisms of inherited and acquired human diseases as well as experimental injury models of this barrier have helped to unravel this interdependence. Key among the consequences of interference with the integrity of the glomerular filtration barrier is the appearance of significant amounts of proteins in the urine. Proteinuria correlates with kidney disease progression and cardiovascular mortality. With specific reference to proteinuria in human and animal disease phenotypes, the following review explores the roles of the endothelial cell, glomerular basement membrane, and the podocyte and attempts to highlight examples of essential crosstalk within this barrier.

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