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Bengt Rippe - One of the best experts on this subject based on the ideXlab platform.

  • a distributed solute model an extended two pore model with application to the Glomerular sieving of ficoll
    American Journal of Physiology-renal Physiology, 2018
    Co-Authors: Carl M Oberg, William H Fissell, Joseph J Groszek, Shuvo Roy, Bengt Rippe
    Abstract:

    One of the many unresolved questions regarding the permeability of the Glomerular Filtration Barrier is the reason behind the marked difference in permeability between albumin and polysaccharide pr...

  • acute reactive oxygen species ros dependent effects of il 1β tnf α and il 6 on the Glomerular Filtration Barrier gfb in vivo
    American Journal of Physiology-renal Physiology, 2015
    Co-Authors: Kristinn Sverrisson, Anna Rippe, Josefin Axelsson, Daniel Asgeirsson, Bengt Rippe
    Abstract:

    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 (Ficoll50-80A), 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.

  • quantification of the electrostatic properties of the Glomerular Filtration Barrier modeled as a charged fiber matrix separating anionic from neutral ficoll
    American Journal of Physiology-renal Physiology, 2013
    Co-Authors: Carl M Oberg, Bengt Rippe
    Abstract:

    In the current study we explore the electrostatic interactions on the transport of anionic Ficoll (aFicoll) vs. neutral Ficoll (nFicoll) over the Glomerular Filtration Barrier (GFB) modeled as a ch...

  • size selectivity of a synthetic high flux and a high cut off dialyzing membrane compared to that of the rat Glomerular Filtration Barrier
    Journal of Membrane Science, 2012
    Co-Authors: Josefin Axelsson, Carl M Oberg, Anna Rippe, Bernd Krause, Bengt Rippe
    Abstract:

    The aim of the present study was to investigate the size-selectivity of two different synthetic dialyzing membranes, having widely differing sieving properties, with respect to their handling of polydispersed fluorescein isothiocyanate (FITC)-Ficoll, FITC-dextran and of proteins, i.e. I-125-human serum albumin (RISA) and I-125-myoglobin (Myo). Are Ficoll and dextran, compared to proteins, "hyperpermeable" across synthetic dialyzing membranes, similar to their behavior across the Glomerular Filtration Barrier (GFB)? A high-flux membrane (HF-Revaclear (R); n = 12) and a high cut-off membrane (HCO; n = 14) in capillary mini-dialyzers were perfused with diluted horse serum. The perfusate contained polydisperse FITC-Ficoll 70/400 or FITC-dextran (mol radius 13-80 angstrom), FITC-Inulin, and, in some experiments, RISA/Myo. After a priming period, sampling of filtrate occurred, and a midpoint plasma sample taken. Filtrate-to-plasma concentration ratios (theta) vs. molecular radius (a(e)) were assessed using HPLC for Ficoll and dextran. Size-selectivity for Ficoll increased in the order: HF-Revaclear (R) < rat glomerulus < HCO. Although the HCO filter showed the highest cut-off, this occurred at the expense of a high permeability to albumin and large Ficoll molecules and a high degree of dispersity of (small) pore radii, as assessed using a log-normal + shunt distributed pore model. According to a two-pore model, the fractional hydraulic conductance accounted for by large pores (alpha(L)) was 8.58 +/- 0.93 x 10(-3) and 1.51 +/- 0.88 x 10(-3) for the HCO and the HF-Revaclear (R), respectively, compared to 4.1 +/- 0.80 x 10(-5) for the rat glomerulus. In conclusion, the HCO filter investigated showed a high theta for myoglobin, similar to that of the GFB. However, the number of large pores was markedly higher and the pore size heterogeneity markedly larger than for the GFB. Membrane permeability was dependent on molecular species and increased in the order: proteins < Ficoll < dextran. (C) 2012 Published by Elsevier B.V. (Less)

  • reduced diffusion of charge modified conformationally intact anionic ficoll relative to neutral ficoll across the rat Glomerular Filtration Barrier in vivo
    American Journal of Physiology-renal Physiology, 2011
    Co-Authors: Josefin Axelsson, Anna Rippe, Kristinn Sverrisson, William H Fissell, Bengt Rippe
    Abstract:

    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, carb...

Jeffrey H Miner - One of the best experts on this subject based on the ideXlab platform.

  • the Glomerular basement membrane as a Barrier to albumin
    Nature Reviews Nephrology, 2013
    Co-Authors: Jung Hee Suh, Jeffrey H Miner
    Abstract:

    The Glomerular basement membrane (GBM) is the central layer of the Glomerular Filtration Barrier and is situated between endothelial cells and podocyte foot processes. The functional importance of the GBM versus that of podocytes and endothelial cells for establishing the Glomerular Filtration Barrier to albumin is still debated. This Review discusses the proposed mechanisms whereby the GBM serves as the major albumin Barrier and describes two genetic kidney diseases that target GBM components. The Glomerular basement membrane (GBM) is the central, non-cellular layer of the Glomerular Filtration Barrier that is situated between the two cellular components—fenestrated endothelial cells and interdigitated podocyte foot processes. The GBM is composed primarily of four types of extracellular matrix macromolecule—laminin-521, type IV collagen α3α4α5, the heparan sulphate proteoglycan agrin, and nidogen—which produce an interwoven meshwork thought to impart both size-selective and charge-selective properties. Although the composition and biochemical nature of the GBM have been known for a long time, the functional importance of the GBM versus that of podocytes and endothelial cells for establishing the Glomerular Filtration Barrier to albumin is still debated. Together with findings from genetic studies in mice, the discoveries of four human mutations affecting GBM components in two inherited kidney disorders, Alport syndrome and Pierson syndrome, support essential roles for the GBM in Glomerular permselectivity. Here, we explain in detail the proposed mechanisms whereby the GBM can serve as the major albumin Barrier and discuss possible approaches to circumvent GBM defects associated with loss of permselectivity.

  • Glomerular basement membrane and related Glomerular disease
    Translational Research, 2012
    Co-Authors: Ying Maggie Chen, Jeffrey H Miner
    Abstract:

    The Glomerular basement membrane (GBM) is lined by fenestrated endothelium from the capillary-lumen side and by interdigitating foot processes of the podocytes from the urinary- space side. These three layers of the Glomerular capillary wall constitute the functional unit of the Glomerular Filtration Barrier. The GBM is assembled through an interweaving of type IV collagen with laminins, nidogen, and sulfated proteoglycans. Mutations in genes encoding LAMB2, COL4A3, COL4A4, and COL4A5 cause Glomerular disease in humans as well as in mice. In addition, laminin α5 mutation in podocytes leads to proteinuria and renal failure in mice. Moreover, more neoepitopes in Goodpasture's disease and for the first time alloepitopes in Alport post-transplantation nephritis have been located in the collagen α5(IV) NC1 domain. These discoveries underscore the importance of the GBM in establishing and maintaining the integrity of the Glomerular Filtration Barrier.

  • maintenance of Glomerular Filtration Barrier integrity requires laminin α5
    Journal of The American Society of Nephrology, 2010
    Co-Authors: Seth Goldberg, Tracy L Adairkirk, Robert M, Jeffrey H Miner
    Abstract:

    Mutation of the mouse laminin alpha5 gene results in a variety of developmental defects, including defects in kidney structure and function. Whereas the total absence of laminin alpha5 results in breakdown of the Glomerular basement membrane (GBM) and failed Glomerular vascularization, a hypomorphic Lama5 mutation (the Lama5(neo) allele) results in proteinuria, hematuria, polycystic kidney disease (PKD), and death 3 to 4 weeks after birth. Here, we examined the role of podocyte-derived laminin alpha5 via podocyte-specific inactivation of Lama5 and podocyte-specific rescue of the Lama5(neo) mutation. Podocyte-specific inactivation of Lama5 resulted in varying degrees of proteinuria and rates of progression to nephrotic syndrome. The GBM of proteinuric mice appeared thickened and "moth-eaten," and podocyte foot processes became effaced. Podocyte-specific restoration of laminin alpha5 production using two distinct strategies in Lama5(neo/neo) mice resulted in the resolution of proteinuria, hematuria, and PKD. These results suggest that the development of normal GBM structure and function requires podocyte-derived laminin alpha5 during and after glomerulogenesis and present a unique mechanism for the pathogenesis of PKD in these mice.

  • update on the Glomerular Filtration Barrier
    Current Opinion in Nephrology and Hypertension, 2009
    Co-Authors: George Jarad, Jeffrey H Miner
    Abstract:

    Purpose of the review The nephrology community lacks a unified view of protein sieving through the Glomerular capillary wall (GCW). The GCW consists of three distinct but closely interacting layers: the fenestrated endothelium, with its glycocalyx; the podocytes, with their interdigitated foot processes and slit diaphragms; and the intervening Glomerular basement membrane (GBM). Proteinuria is associated with abnormalities in any one layer, suggesting that each contributes to the Glomerular Filtration Barrier (GFB). Proteinuria can also be induced in the context of a normal GCW. Here we review some classic studies as well as some newer concepts and present competing hypotheses about the GFB.

Maciej Jankowski - One of the best experts on this subject based on the ideXlab platform.

  • intracellular calcium signaling regulates Glomerular Filtration Barrier permeability the role of the pkgiα dependent pathway
    FEBS Letters, 2016
    Co-Authors: Agnieszka Piwkowska, Dorota Rogacka, Irena Audzeyenka, Malgorzata Kasztan, Stefan Angielski, Maciej Jankowski
    Abstract:

    Podocytes are dynamic polarized cells that lie on the surface of Glomerular capillaries and comprise an essential component of the Glomerular Filtration Barrier. Insulin provoked a sustained, approximately 70%, increase in intracellular calcium concentration in podocytes. RT-PCR revealed the presence of mRNA encoding sarco/endoplasmic reticulum calcium ATPase isoforms 1-3, and plasma membrane Ca(2+) pump (PMCA) isoforms 1,3,4; mRNA levels were depressed by the addition of insulin. Inhibitors of PMCA, and the Na(+) -Ca(2+) exchanger, increased podocyte permeability to albumin, induced dimerization of protein kinase G type I alpha (PKGIα), and activation of PKGIα-dependent signaling. These data suggest the involvement of calcium and PKGIα signaling in insulin-enhanced Filtration Barrier permeability in podocytes.

  • insulin increases Glomerular Filtration Barrier permeability through pkgiα dependent mobilization of bkca channels in cultured rat podocytes
    Biochimica et Biophysica Acta, 2015
    Co-Authors: Agnieszka Piwkowska, Dorota Rogacka, Irena Audzeyenka, Malgorzata Kasztan, Stefan Angielski, Maciej Jankowski
    Abstract:

    Abstract Podocytes are highly specialized cells that wrap around Glomerular capillaries and comprise a key component of the Glomerular Filtration Barrier. They are uniquely sensitive to insulin; like skeletal muscle and fat cells, they exhibit insulin-stimulated glucose uptake and express glucose transporters. Podocyte insulin signaling is mediated by protein kinase G type I (PKGI), and it leads to changes in Glomerular permeability to albumin. Here, we investigated whether large-conductance Ca 2 + -activated K + channels (BK Ca ) were involved in insulin-mediated, PKGIα-dependent Filtration Barrier permeability. Insulin-induced Glomerular permeability was measured in glomeruli isolated from Wistar rats. Transepithelial albumin flux was measured in cultured rat podocyte monolayers. Expression of BK Ca subunits was detected by RT-PCR. BK Ca , PKGIα, and upstream protein expression were examined in podocytes with Western blotting and immunofluorescence. The BK Ca –PKGIα interaction was assessed with co-immunoprecipitation. RT-PCR showed that primary cultured rat podocytes expressed mRNAs that encoded the pore-forming α subunit and four accessory β subunits of BK Ca . The BK Ca inhibitor, iberiotoxin (ibTX), abolished insulin-dependent Glomerular albumin permeability and PKGI-dependent transepithelial albumin flux. Insulin-evoked albumin permeability across podocyte monolayers was also blocked with BK Ca siRNA. Moreover, ibTX blocked insulin-induced disruption of the actin cytoskeleton and changes in the phosphorylation of PKG target proteins, MYPT1 and RhoA. These results indicated that insulin increased Filtration Barrier permeability through mobilization of BK Ca channels via PKGI in cultured rat podocytes. This molecular mechanism may explain podocyte injury and proteinuria in diabetes.

  • insulin increases Glomerular Filtration Barrier permeability through dimerization of protein kinase g type iα subunits
    Biochimica et Biophysica Acta, 2013
    Co-Authors: Agnieszka Piwkowska, Dorota Rogacka, Malgorzata Kasztan, Stefan Angielski, Maciej Jankowski
    Abstract:

    The increase in the permeability of the Glomerular Barrier Filtration to albumin is a well-known feature of diabetic microvasculature and a negative prognostic factor for vascular complications. However, the underlying mechanisms are incompletely understood. We demonstrated recently that superoxide anion generation increases dimerization of protein kinase G type Iα (PKGIα) subunits, leading to podocyte dysfunction. Here we investigated whether high insulin concentration is involved in PKGI-dependent hyperpermeability of the diabetic Glomerular Filtration Barrier. We assessed changes in insulin-induced Glomerular permeability by measuring Glomerular capillary permeability to albumin in isolated glomeruli from Wistar and obese and lean Zucker rats and transmembrane albumin flux in cultured rat podocytes. Expression of PKGIα and upstream proteins was confirmed in the podocytes using Western blotting and immunofluorescence. Insulin (300nM, 5min) increased NAD(P)H-dependent Glomerular albumin permeability in Wistar rats and PKGI-dependent transmembrane albumin flux in cultured podocytes. Podocyte exposure to insulin in non-reducing conditions increased PKGIα interprotein disulfide bond formation, altered the phosphorylation of the PKG target proteins MYPT1 and MLC, and disrupted the actin cytoskeleton. The role of NADPH oxidase (NOX) in insulin-induced reactive oxygen species (ROS) generation and insulin-evoked increases in albumin permeability in podocytes was confirmed with NOX2 and NOX4 siRNA. Glomerular albumin permeability was increased in hyperinsulinemic Zucker obese rats with isolated glomeruli showing increased expression of PKGIα and NOX4. Taken together, these data demonstrate that insulin increases Glomerular Barrier albumin permeability via a PKGI-dependent mechanism involving NAD(P)H-dependent generation of superoxide anion. These findings reveal a role for insulin in the pathophysiology of diabetic Glomerular nephropathy.

Anna Rippe - One of the best experts on this subject based on the ideXlab platform.

  • acute reactive oxygen species ros dependent effects of il 1β tnf α and il 6 on the Glomerular Filtration Barrier gfb in vivo
    American Journal of Physiology-renal Physiology, 2015
    Co-Authors: Kristinn Sverrisson, Anna Rippe, Josefin Axelsson, Daniel Asgeirsson, Bengt Rippe
    Abstract:

    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 (Ficoll50-80A), 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.

  • size selectivity of a synthetic high flux and a high cut off dialyzing membrane compared to that of the rat Glomerular Filtration Barrier
    Journal of Membrane Science, 2012
    Co-Authors: Josefin Axelsson, Carl M Oberg, Anna Rippe, Bernd Krause, Bengt Rippe
    Abstract:

    The aim of the present study was to investigate the size-selectivity of two different synthetic dialyzing membranes, having widely differing sieving properties, with respect to their handling of polydispersed fluorescein isothiocyanate (FITC)-Ficoll, FITC-dextran and of proteins, i.e. I-125-human serum albumin (RISA) and I-125-myoglobin (Myo). Are Ficoll and dextran, compared to proteins, "hyperpermeable" across synthetic dialyzing membranes, similar to their behavior across the Glomerular Filtration Barrier (GFB)? A high-flux membrane (HF-Revaclear (R); n = 12) and a high cut-off membrane (HCO; n = 14) in capillary mini-dialyzers were perfused with diluted horse serum. The perfusate contained polydisperse FITC-Ficoll 70/400 or FITC-dextran (mol radius 13-80 angstrom), FITC-Inulin, and, in some experiments, RISA/Myo. After a priming period, sampling of filtrate occurred, and a midpoint plasma sample taken. Filtrate-to-plasma concentration ratios (theta) vs. molecular radius (a(e)) were assessed using HPLC for Ficoll and dextran. Size-selectivity for Ficoll increased in the order: HF-Revaclear (R) < rat glomerulus < HCO. Although the HCO filter showed the highest cut-off, this occurred at the expense of a high permeability to albumin and large Ficoll molecules and a high degree of dispersity of (small) pore radii, as assessed using a log-normal + shunt distributed pore model. According to a two-pore model, the fractional hydraulic conductance accounted for by large pores (alpha(L)) was 8.58 +/- 0.93 x 10(-3) and 1.51 +/- 0.88 x 10(-3) for the HCO and the HF-Revaclear (R), respectively, compared to 4.1 +/- 0.80 x 10(-5) for the rat glomerulus. In conclusion, the HCO filter investigated showed a high theta for myoglobin, similar to that of the GFB. However, the number of large pores was markedly higher and the pore size heterogeneity markedly larger than for the GFB. Membrane permeability was dependent on molecular species and increased in the order: proteins < Ficoll < dextran. (C) 2012 Published by Elsevier B.V. (Less)

  • reduced diffusion of charge modified conformationally intact anionic ficoll relative to neutral ficoll across the rat Glomerular Filtration Barrier in vivo
    American Journal of Physiology-renal Physiology, 2011
    Co-Authors: Josefin Axelsson, Anna Rippe, Kristinn Sverrisson, William H Fissell, Bengt Rippe
    Abstract:

    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, carb...

  • loss of size selectivity of the Glomerular Filtration Barrier in rats following laparotomy and muscle trauma
    American Journal of Physiology-renal Physiology, 2009
    Co-Authors: Josefin Axelsson, Irma Mahmutovic, Anna Rippe, Bengt Rippe
    Abstract:

    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 reabsor...

  • nature of Glomerular capillary permeability changes following acute renal ischemia reperfusion injury in rats
    American Journal of Physiology-renal Physiology, 2006
    Co-Authors: Catarina Rippe, Daniel Asgeirsson, Anna Rippe, Anna Larsson, Bengt Rippe
    Abstract:

    This study was performed to evaluate the alterations of Glomerular Filtration Barrier characteristics following acute renal ischemia-reperfusion (I/R). Ischemia was induced in anesthetized rats by ...

Simon C Satchell - One of the best experts on this subject based on the ideXlab platform.

  • an in vitro model of the Glomerular capillary wall using electrospun collagen nanofibres in a bioartificial composite basement membrane
    PLOS ONE, 2011
    Co-Authors: Sadie C Slater, Vince Beachley, Tom Hayes, Daming Zhang, Gavin I Welsh, Moin A Saleem, Peter W Mathieson, Xuejun Wen, Simon C Satchell
    Abstract:

    The filtering unit of the kidney, the glomerulus, contains capillaries whose walls function as a biological sieve, the Glomerular Filtration Barrier. This comprises layers of two specialised cells, Glomerular endothelial cells (GEnC) and podocytes, separated by a basement membrane. Glomerular Filtration Barrier function, and dysfunction in disease, remains incompletely understood, partly due to difficulties in studying the relevant cell types in vitro. We have addressed this by generation of unique conditionally immortalised human GEnC and podocytes. However, because the Glomerular Filtration Barrier functions as a whole, it is necessary to develop three dimensional co-culture models to maximise the benefit of the availability of these cells. Here we have developed the first two tri-layer models of the Glomerular capillary wall. The first is based on tissue culture inserts and provides evidence of cell-cell interaction via soluble mediators. In the second model the synthetic support of the tissue culture insert is replaced with a novel composite bioartificial membrane. This consists of a nanofibre membrane containing collagen I, electrospun directly onto a micro-photoelectroformed fine nickel supporting mesh. GEnC and podocytes grew in monolayers on either side of the insert support or the novel membrane to form a tri-layer model recapitulating the human Glomerular capillary in vitro. These models will advance the study of both the physiology of normal Glomerular Filtration and of its disruption in Glomerular disease.

  • functional distinctions in cytosolic calcium regulation between cells of the Glomerular Filtration Barrier
    Cell Calcium, 2010
    Co-Authors: Rebecca R Foster, Gavin I Welsh, Peter W Mathieson, Simon C Satchell, David O Bates, Robin Marlow, Mathew D Wherlock, Debora Pons, Moin A Saleem
    Abstract:

    The importance of intracellular calcium ([Ca2+]i) regulation in the Glomerular Filtration Barrier (GFB) has recently been highlighted by mutations in the cation channel TRPC6, resulting in a renal-specific phenotype. We examined the effects of FFA, a tool that can activate TRPC6, on [Ca2+]i in human conditionally immortalised Glomerular endothelial cells (ciGEnC) and human podocytes (ciPod) that form the GFB. Changes in [Ca2+]i stimulated by FFA were measured in Fura 2-AM loaded cells. In GEnC, cell activation by FFA was dependent on external Ca2+, yet in ciPod it was not. Depletion of internal Ca2+ stores with thapsigargin did not affect cell activation by FFA in ciGEnC, but inhibited it in ciPod in a nephrin-dependent manner, demonstrated using nephrin deficient (ND) ciPod in conjunction with nephrin rescue experiments. FFA induced [Ca2+]i store release in ciPod, but not in ciGEnC or ND ciPod. In parallel, there were differences in the localisation of overexpressed TRPC6 between ciGEnC and ciPod. Furthermore, co-transfection of nephrin with TRPC6 in HEK293 cells reduced the FFA-induced increase in [Ca2+]i and nephrin clustering altered TRPC6 distribution. In conclusion, cell activation by FFA in podocytes stimulates the opening of a Ca2+ channel, probably TRPC6, in a nephrin-dependent manner with a different activation profile to GEnC.

  • Glomerular endothelial cell fenestrations an integral component of the Glomerular Filtration Barrier
    American Journal of Physiology-renal Physiology, 2009
    Co-Authors: Simon C Satchell, Filip Braet
    Abstract:

    Glomerular endothelial cell (GEnC) fenestrations are analogous to podocyte Filtration slits, but their important contribution to the Glomerular Filtration Barrier has not received corresponding attention. GEnC fenestrations are transcytoplasmic holes, specialized for their unique role as a prerequisite for Filtration across the Glomerular capillary wall. Glomerular Filtration rate is dependent on the fractional area of the fenestrations and, through the glycocalyx they contain, GEnC fenestrations are important in restriction of protein passage. Hence, dysregulation of GEnC fenestrations may be associated with both renal failure and proteinuria, and the pathophysiological importance of GEnC fenestrations is well characterized in conditions such as preeclampsia. Recent evidence suggests a wider significance in repair of Glomerular injury and in common, yet serious, conditions, including diabetic nephropathy. Study of endothelial cell fenestrations is challenging because of limited availability of suitable in vitro models and by the requirement for electron microscopy to image these sub-100-nm structures. However, extensive evidence, from Glomerular development in rodents to in vitro studies in human GEnC, points to vascular endothelial growth factor (VEGF) as a key inducer of fenestrations. In systemic endothelial fenestrations, the intracellular pathways through which VEGF acts to induce fenestrations include a key role for the fenestral diaphragm protein plasmalemmal vesicle-associated protein-1 (PV-1). The role of PV-1 in GEnC is less clear, not least because of controversy over existence of GEnC fenestral diaphragms. In this article, the structure-function relationships of GEnC fenestrations will be evaluated in depth, their role in health and disease explored, and the outlook for future study and therapeutic implications of these peculiar structures will be approached.