bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pentosan Polysulfate Decreases Proliferation and Net Extracellular Matrix Production in Mouse Mesangial Cells
Authors: ELLIOT SHARON J. , STRIKER LILIANE J. , STETLER-STEVENSON WILLIAM G. , JACOT TERRY A. , STRIKER GARY E. 
Published: April 2021

Abstract.
Glomerulosclerosis is characterized by extracellular matrix accumulation and is often associated with mesangial cell proliferation. Heparin-like molecules have been shown to decrease glomerulosclerosis in vivo, although their cellular site and mechanism of action is still unclear. In this study, a line of glomerular mesangial cells derived from normal mice was used to determine whether pentosan polysulfate (PPS) inhibited proliferation and altered extracellular matrix turnover. Cells treated with PPS showed a decrease in cell number beginning 24 h after treatment, which was maintained for 5 d. For matrix accumulation and degradation studies, cells were treated for 5 d and collagen types I and IV protein were measured by enzyme-linked immunosorbent assay as well as matrix metalloproteinases (MMP) measured by zymography. Collagen types I and type IV were significantly decreased in the media (P < 0.0001) and cell layer (P < 0.005) after treatment with PPS but not after treatment with heparin. By zymography, MMP-2 was significantly increased after treatment with PPS (P < 0.001) and heparin (P < 0.05). PPS and heparin also decreased MMP-9 (P < 0.001) after treatment. Reverse zymography showed the presence of tissue inhibitors of metalloproteinases (TIMP)-1 and -2 in control mesangial cells. Treatment with PPS and heparin increased TIMP-1. In addition, TIMP-3 was found in the medium of treated but not control cells. In conclusion, PPS alters extracellular matrix turnover through the induction of MMP-2 and alterations in the TIMP profile and may be useful in decreasing progressive glomerulosclerosis.
Ganglioside GM2-Activator Protein and Vesicular Transport in Collecting Duct Intercalated Cells
Authors: MUNDEL THOMAS M. , HEID HANS W. , MAHURAN DON J. , KRIZ WILHELM , MUNDEL PETER 
Published: April 2021

Abstract.
This study describes the molecular characterization of an antigen defined by an autoantibody from a woman with habitual abortion as GM2-activator protein. The patient showed no disorder of renal function. Accidentally with routine serum screening for autoantibodies, an immunoreactivity was found in kidney collecting duct intercalated cells. Three distinct patterns of immunostaining of intercalated cells were observed: staining of the apical pole, basolateral pole, and diffuse cytoplasmic labeling. Ultrastructurally, the immunoreactivity was associated with “studs,” which represent the cytoplasmic domain of the vacuolar proton pump in intercalated cells. This pump is subjected to a shuttling mechanism from cytoplasmic stores to the cell membrane, which exclusively occurs in intercalated cells. Peptide sequences of a 23-kD protein purified from rat kidney cortex showed complete identity with corresponding sequences of GM2-activator protein. In the brain, GM2-activator protein is required for hexosaminidase A to split a sugar from ganglioside GM2. Because neither ganglioside GM2 nor GM1 (its precursor) is present in significant amounts in the kidney, the previous finding that this tissue contains the highest level of activator protein in the body was confusing. In this study, a novel role for GM2-activator protein in intercalated cells is proposed, and possible roles in the shuttling mechanism are discussed.
Osteopontin Expression in Fetal and Mature Human Kidney
Authors: HUDKINS KELLY L. , GIACHELLI CECILIA M. , YAN CUI  , COUSER WILLIAM G. , JOHNSON RICHARD J. , ALPERS CHARLES E. 
Published: April 2021

Abstract.
Osteopontin is a secreted phosphoprotein that is expressed by normal kidney, and has been associated with a number of functions including cell adhesion, migration, signaling, and biomineralization. Although there is a vast literature detailing osteopontin localization in various rodent models of both development and disease, this article presents the first comprehensive description of osteopontin localization in human kidney. In this study, immunohistochemistry, immunoelectron microscopy, in situ hybridization, and Northern blotting are used to analyze osteopontin protein and mRNA expression in human fetal and normal mature renal tissue. Osteopontin is expressed in the human embryonic renal tubular epithelium beginning on approximately day 75 to 80 of gestation. In the fetal kidney, osteopontin can also be seen occasionally expressed in the ureteric buds and in some interstitial cells. As localized at the protein and mRNA level, the tubular expression of osteopontin increases with increasing gestational age and persists into adulthood. In the normal adult kidney, osteopontin is localized primarily to the distal nephron and is strongly expressed by the thick ascending limb of the loops of Henle. Osteopontin expression can also be observed in some collecting duct epithelium. In cases that exhibit foci of interstitial fibrosis and an associated influx of interstitial macrophages, osteopontin expression is significantly upregulated in all tubular segments, including proximal tubules.
Prominence of Cell-Mediated Immunity Effectors in “Pauci-Immune” Glomerulonephritis
Authors: CUNNINGHAM MALCOLM A. , HUANG XIAO RU , DOWLING JOHN P. , TIPPING PETER G. , HOLDSWORTH STEPHEN R. 
Published: April 2021

Abstract.
The majority of patients with rapidly progressive crescentic glomerulonephritis show histologic features of extensive necrosis and focal and segmental proliferation with fibrin production, but little or absent Ig deposition in the glomerulus. This subcategory of the disease, labeled “pauci-immune” glomerulonephritis, has recently been shown to be associated with the presence of antineutrophil cytoplasmic antibody in the patient's circulation (but not within the glomerulus). The absence of the effectors of humoral immunity at the site of renal injury led to this investigation of the contribution of cell-mediated immunity to the glomerular injury in this form of glomerulonephritis. In 15 patients presenting acutely with pauci-immune glomerulonephritis, CD3-positive T cells (3.7 ± 2.5 [mean ± SD] cells per glomerular cross section, [c/gcs]), CD45RO-positive T cells (2.7 ± 1.9 c/cgs), macrophages (7.3 ± 6.1 c/gcs), fibrin (3+), and endothelial-associated tissue factor were demonstrated to be prominent in glomeruli. These mediators were absent in a group of 12 patients with thin basement membrane disease and only occasionally observed in a group of eight patients with “humorally mediated” (noncrescentic) glomerulonephritis. Thus, in pauci-immune glomerulonephritis, there is the development of significant cell-mediated immunity with activated T cells, macrophages, tissue factor, and fibrin at the site of glomerular injury, suggesting that this glomerular disease is most likely a manifestation of T cell-directed cognate immune injury.
The Intrarenal Vascular Lesions Associated with Primary Antiphospholipid Syndrome
Authors: NOCHY DOMINIQUE , DAUGAS ERIC , DROZ DOMINIQUE , BEAUFILS HELENE , GRÜNFELD JEAN-PIERRE , PIETTE JEAN-CHARLES , BARIETY JEAN , HILL GARY 
Published: April 2021

Abstract.
Even 10 yr after the identification of the antiphospholipid syndrome (APS), renal involvement in the course of APS is still relatively unrecognized, and is probably underestimated. The association of anticardiolipin antibodies and/or lupus anticoagulant with the development of a vaso-occlusive process involving numerous organs is now confirmed. In a multicenter study, 16 cases of “primary” APS (PAPS) were found and followed for 5 yr or more, all with renal biopsy. In all 16 cases of PAPS, there was a vascular nephropathy characterized by small vessel vaso-occlusive lesions associated with fibrous intimal hyperplasia of interlobular arteries (12 patients), recanalizing thrombi in arteries and arterioles (six patients), and focal cortical atrophy (10 patients). In combination, these led to progressive destruction of the kidney, accelerated by acute glomerular and arteriolar microangiopathy in five patients. Focal cortical atrophy is a distinctive lesion, present in 10 biopsies, and likely represents the histologic and functional renal analogue to the multiple cerebral infarcts detected on imaging studies. The clinical hallmark of this vascular nephropathy in PAPS is systemic hypertension, only variably associated with renal insufficiency, proteinuria, or hematuria. The ensemble of histologic renal lesions defined in this study should aid in the separation of the lesions found in cases of secondary APS, especially systemic lupus erythematosus, into those lesions related to APS and those related to the underlying disease.
“The FSGS Factor”
Authors: SHARMA MUKUT , SHARMA RAM , MCCARTHY ELLEN T. , SAVIN VIRGINIA J. 
Published: April 2021

Abstract.
A circulating causative factor has been postulated in focal segmental glomerulosclerosis (FSGS). It has been shown that serum or plasma from some FSGS increases glomerular albumin permeability (Palb) in vitro. Palb greater than 0.5 (i.e., FS activity) is associated with recurrence after transplantation. Specimens from 15 FSGS patients were studied to document the presence of a permeability factor, to isolate this factor, to characterize its biochemical properties, and to show its effect in vivo. Total lipids were extracted by chloroform/methanol (2:1); FS activity was absent from total lipid extract. Chylomicrons and lipoproteins were removed from the plasma with dextran sulfate, followed by sequential precipitation of proteins at 50 and 70% ammonium sulfate saturation. FS activity was retained in the 70% ammonium sulfate supernatant and exhibited a 100-fold purification. FS activity was lost after heating at 100°C for 10 min or after protease digestion. Under nondenaturing conditions, electrophoresis of the FSGS 70% supernatant showed a prominent low molecular weight band that was not evident in the 70% supernatant from normal plasma. Dialysis and centrifugation-based membrane ultrafiltration of the FSGS factor indicated a molecular size between 30 and 50 kD. Injection of the 70% FSGS supernatant into rats caused a threefold increase in urine protein in collections from 6 to 24 h after injection. No increase in proteinuria occurred in rats injected with 70% supernatant from normal individuals. It is concluded that the FSGS factor is a low molecular weight protein with the potential to increase Palb in vitro and to cause proteinuria in vivo.
Intranephron Distribution and Regulation of Endothelin-Converting Enzyme-1 in Cyclosporin A-Induced Acute Renal Failure in Rats
Authors: NAKAYAMA YUSHI , NONOGUCHI HIROSHI , KIYAMA SHIGERU , IKEBE MIKA , TASHIMA YUKA , SHIMADA KOHEI , TANZAWA KAZUHIKO , TOMITA KIMIO 
Published: April 2021

Abstract.
Endothelin-1 (ET-1) is thought to play a significant role in acute renal failure induced by cyclosporin A (CsA). The cDNA sequence encoding endothelin-converting enzyme-1 (ECE-1), which produces the active form of ET-1 from big ET-1, was recently reported. To elicit the role of ECE-1 in the glomerular and tubular dysfunction induced by CsA, the effects of CsA on mRNA and protein expression of ECE-1 in rat kidney and on mRNA expression of prepro-ET-1 and ET A- and B-type receptors in glomeruli were studied. ECE-1 mRNA was detected in glomeruli and in whole nephron segments. ECE-1 mRNA expression was downregulated in all nephron segments at 24 h after CsA injection. Protein levels were also downregulated in glomeruli and in the outer and inner medulla. CsA rapidly increased prepro-ET-1 mRNA expression in glomeruli at 30 to 60 min after injection; this rapid increase was followed by an increase in plasma ET-1 levels. These increases were followed by decreased expression of ECE-1, ET A-type receptor, and ET B-type receptor mRNA at 6 h after injection, and serum creatinine levels were increased at 24 h after CsA injection. It is suggested that downregulation of glomerular and tubular ECE-1 expression may be caused by increased ET-1 synthesis in CsA-induced acute renal failure.
Asymmetric Dimethylarginine Plasma Concentrations Differ in Patients with End-Stage Renal Disease
Authors: KIELSTEIN JAN T. , BÖGER RAINER H. , BODE-BÖGER STEFANINE M. , SCHÄFFER JÜRGEN , BARBEY MARK , KOCH KARL M. , FRÖLICH JÜRGEN C. 
Published: April 2021

Abstract.
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase. Its concentration is elevated in patients with end-stage renal disease (ESRD), in part because it is excreted via the kidneys. In this study, the plasma concentrations of ADMA, symmetric dimethylarginine, and L-arginine were determined in relation to plasma nitrate levels (as an index of NO formation) for a group of 80 patients with ESRD. The effects of two treatment methods, i.e., hemodialysis (HD) and peritoneal dialysis (PD), and the role of the presence of atherosclerotic disease were evaluated. Forty-three patients receiving HD and 37 patients receiving PD were compared with healthy control subjects. Plasma L-arginine and dimethylarginine levels were determined by HPLC, using precolumn derivatization with o-phthaldialdehyde. Plasma nitrate levels were determined by gas chromatography-mass spectrometry. Predialysis ADMA concentrations in HD-treated patients were approximately sixfold higher than those in the control group (6.0 ± 0.5 versus 1.0 ± 0.1 μmol/L; P < 0.05). Plasma nitrate concentrations were significantly lower in HD-treated patients, which suggests that ADMA may inhibit NO synthase. In contrast, plasma ADMA levels and nitrate concentrations in PD-treated patients were similar to those in control subjects. Plasma L-arginine concentrations were not significantly decreased in patients with ESRD. ADMA concentrations were significantly decreased 5 h after HD, compared with baseline values. ADMA levels were significantly higher in HD-treated patients with manifest atherosclerotic disease than in HD-treated patients without atherosclerotic disease (7.31 ± 0.70 versus 3.95 ± 0.52 μmol/L; P < 0.05). This study confirms that ADMA is accumulated in ESRD. PD-treated patients exhibit significantly lower ADMA levels than do HD-treated patients. Accumulation of ADMA may be a risk factor for the development of endothelial dysfunction and cardiovascular disease in patients with ESRD.
Quantifying the Effect of Changes in the Hemodialysis Prescription on Effective Solute Removal with a Mathematical Model
Authors: CLARK WILLIAM R. , LEYPOLDT JOHN K. , HENDERSON LEE W. , MUELLER BRUCE A. , SCOTT MERI KAY , VONESH EDWARD F. 
Published: April 2021

Abstract.
One potential benefit of chronic hemodialysis (HD) regimens of longer duration or greater frequency than typical three-times-weekly schedules is enhanced solute removal over a relatively wide molecular weight spectrum of uremic toxins. This study assesses the effect of variations in HD frequency (F: per week), duration (T: min per treatment), and blood/dialysate flow rates (Q
B/Q
D: ml/min) on steady-state concentration profiles of five surrogates: urea (U), creatinine (Cr), vancomycin (V), inulin (I), and β2-microglobulin (β2M). The regimens assessed for an anephric 70-kg patient were: A (standard): F = 3, T = 240, Q
B = 350, Q
D = 600; B (daily/short-time): F = 7, T = 100, Q
B = 350, Q
D = 600; C/D/E (low-flow/long-time): F = 3/5/7, T = 480, Q
B = 300, Q
D = 100. HD was simulated with a variable-volume double-pool model, which was solved by numerical integration (Runge-Kutta method). Endogenous generation rates (G) for U, Cr, and β2M were 6.25, 1.0, and 0.17 mg/min, respectively; constant infusion rates for V and I of 0.2 and 0.3 mg/min, respectively, were used to simulate middle molecule (MM) G values. Intercompartment clearances of 600, 275, 125, 90, and 40 ml/min were used for U, Cr, V, I, and β2M, respectively, For each solute/regimen combination, the equivalent renal clearance (EKR: ml/min) was calculated as a dimensionless value normalized to the regimen A EKR, which was 13.4, 10.8, 6.6, 3.7, and 4.8 ml/min for U, Cr, V, I, and β2M, respectively. For regimens B, C, D, and E, respectively, these normalized EKR values were U: 1.04, 0.96, 1.58, and 2.22; Cr: 1.03, 1.08, 1.80, and 2.55; V: 1.06, 1.32, 2.21, and 3.12; I: 1.05, 1.54, 2.57, and 3.62; β2M: 1.00, 1.27, 1.73, and 2.19. The extent of post-HD rebound (%) was highest for regimens A and B, ranging from 16% (urea) to 50% (inulin), and lowest for regimen E, ranging from 6% (urea) to 28% (β2M). The following conclusions can be made: (1) Relative to a standard three-times-weekly HD regimen of approximately the same total (weekly) treatment duration, a daily/short-time regimen results in modest (3 to 6%) increases in effective small solute and MM removal. (2) Relative to a standard three-times-weekly HD regimen, a three-times-weekly low-flow/long-time regimen results in comparable effective small solute removal and progressive increases in MM and β2M removal. A daily low-flow/long-time regimen substantially increases the effective removal of all solutes.
The Antioxidant N-Acetylcysteine Induces Mesangial Cells to Create Three-Dimensional Cytoarchitecture That Underlies Cellular Differentiation
Authors: KITAMURA MASANORI 
Published: April 2021

Abstract.
Prolonged culture of mesangial cells produces multifocal nodular structures, i.e., “hillocks,” consisting of cells and extracellular matrix. Hillock formation is associated with induction of a differentiated phenotype of mesangial cells, with suppressed mitogenesis and downregulation of α-smooth muscle actin (α-SMA). Currently, little is understood regarding physiologically relevant factors that facilitate this cytodifferentiation. This study explores whether and how the cellular redox state modulates hillock formation. Exposure of confluent rat mesangial cells to the antioxidant N-acetylcysteine (NAC), an inducer of glutathione, dramatically facilitated hillock formation. This effect was mimicked by external addition of the reduced form of glutathione ethyl ester. In contrast, the oxidizing agents diamide and menadione inhibited the development of hillocks triggered by either NAC, glutathione, or prolonged culture. The induction of hillocks by NAC was correlated with downregulation of α-SMA as well as attenuated activity of the CArG box element (the cis-element relevant to the expression of the α-SMA gene and growth-associated genes). These results indicate that, by a redox-sensitive mechanism, NAC induces mesangial cells to create three-dimensional cytoarchitecture that underlies cellular differentiation.
IFN-γ Mediates Crescent Formation and Cell-Mediated Immune Injury in Murine Glomerulonephritis
Authors: KITCHING A. RICHARD , HOLDSWORTH STEPHEN R. , TIPPING PETER G. 
Published: April 2021

Abstract.
Features of crescentic glomerulonephritis suggest that it results from a T helper 1 (Th1) nephritogenic immune response. Interferon-γ (IFN-γ), produced by Th1 cells, is involved in T cell-directed macrophage activation in effector Th1 responses. The hypothesis that endogenous IFN-γ contributes to the development of crescentic glomerulonephritis was tested by comparing the development of glomerulonephritis (induced by a planted antigen) and immune responses in normal C57BL/6 mice (IFN-γ +/+) and in mice genetically deficient in IFN-γ (IFN-γ -/-). Ten days after the initiation of glomerulonephritis, IFN-γ -/- mice developed fewer glomerular crescents (5 ± 1% versus 26 ± 3%, P < 0.005), less severe glomerular injury, and less renal impairment. Effectors of delayed-type hypersensitivity (CD4+ T cells, macrophages, and fibrin) in glomeruli were reduced in IFN-γ -/- mice. Skin delayed-type hypersensitivity to sheep globulin was reduced. Total antigen-specific Ig and splenocyte interleukin-2 production were unchanged, but antigen-specific serum IgG2a was reduced. Markers of an antigen-specific Th2 response (serum IgG1, splenocyte interleukin-4) were unchanged. Studies 22 d after the initiation of glomerulonephritis showed that IFN-γ -/- mice still had fewer crescents (11 ± 2% versus 22 ± 3%, P = 0.02) and glomerular CD4+ T cells and macrophages than IFN-γ +/+ mice. These studies demonstrate that endogenous IFN-γ mediates crescentic glomerulonephritis by promoting cell-mediated immune injury. They support the hypothesis that crescentic glomerulonephritis is a manifestation of a Th1 nephritogenic immune response.
Underglycosylation of IgA1 Hinge Plays a Certain Role for Its Glomerular Deposition in IgA Nephropathy
Authors: HIKI YOSHIYUKI , KOKUBO TOHRU , IWASE HITOO , MASAKI YOSHIHIKO , SANO TAKASHI , TANAKA ATSUSHI , TOMA KAZUNORI , HOTTA KYOKO , KOBAYASHI YUTAKA 
Published: April 2021

Abstract.
This study was performed to isolate and investigate the IgA1 that could accumulate in glomeruli (glomerulophilic IgA1). IgA1 was fractionated by the electric charge and the reactivity to Jacalin. Serum IgA1 of IgA nephropathy patients was separated and fractionated using a Jacalin column and subsequent ion-exchange chromatography. The fractions were divided into three groups of relatively cationic (C), neutral (N), and anionic (A). IgA1 was also divided into Jacalin low (L), intermediate (I), and high (H) affinity fractions by serial elution using 25, 100, and 800 mM galactose. The left kidneys of Wistar rats were perfused with 2, 5, or 10 mg of each group of IgA1. The rats were sacrificed 15 min, 30 min, 3 h, or 24 h after the perfusion. The accumulation of each IgA1 in the glomeruli was then observed by immunofluorescence. The IgA1 of the fractions N and H separated by the two methods was definitely accumulated in the rat glomeruli with a similar pattern. The electrophoresis revealed that the macromolecular IgA1 was increased in fraction H compared with other fractions. Therefore, Jacalin high-affinity IgA1 (fraction H) was applied on a diethylaminoethyl column and divided into electrically cationic (HC), neutral (HN), and anionic (HA). Only the asialo-Galβ1,3GalNAc chain was identified in the fraction HN IgA1 by gas-phase hydrazinolysis. Furthermore, the IgA1 fraction was strongly recognized by peanut agglutinin, Vicia Villosa lectins, and antisynthetic hinge peptide antibody. These results indicated that the IgA1 molecules having the underglycosylated hinge glycopeptide played a certain role in the glomerular accumulation of IgA1 in IgA nephropathy.