bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiotensin II-Stimulated Nitric Oxide Release from Porcine Pulmonary Endothelium Is Mediated by Angiotensin IV
Authors: HILL-KAPTURCZAK NATHALIE , KAPTURCZAK MATTHIAS H. , BLOCK EDWARD R. , PATEL JAWAHARLAL M. , MALINSKI TADEUSZ , MADSEN KIRSTEN M. , TISHER C. CRAIG
Published: April 2021

In this study, a nitric oxide (NO) sensor was used to examine the ability of angiotensin II (AngII), AngIV, and bradykinin (Bk) to stimulate NO release from porcine pulmonary artery (PPAE) and porcine aortic endothelial (PAE) cells and to explore the mechanism of the AngII-stimulated NO release. Physiologic concentrations of AngII, but not Bk, caused release of NO from PPAE cells. In contrast, Bk, but not AngII, stimulated NO release from PAE cells. AngII-stimulated NO release from PPAE cells required extracellular L-arginine and was inhibited by L-nitro-arginine methyl ester. AT1 and AT2 receptor inhibition had no affect on AngII-mediated NO release or activation of NO synthase (NOS). AngIV, and AngII metabolite with binding sites that are pharmacologically distinct from the classic AngII receptors, stimulated considerably greater NO release and greater endothelial-type constitutive NOS activity than the same amount of AngII. The AngIV receptor antagonist, divalinal AngIV, blocked both AngII- and AngIV-mediated NO release as well as NOS activation. The results demonstrate that AngIV and the AngIV receptor are responsible, at least in part, for AngII-stimulated NO release and the associated endothelium-dependent vasorelaxation. Furthermore, these results suggest that differences exist in both AngII- and Bk-mediated NO release between PPAE and PAE cells, which may reflect important differences in response to these hormones between vascular beds.
Role of Xanthine Oxidase in Passive Heymann Nephritis in Rats
Authors: GWINNER WILFRIED , PLASGER JENS , BRANDES RALF P. , KUBAT BIRGIT , SCHULZE MATTHIAS , REGELE HEINZ , KERJASCHKI DONTSCHO , OLBRICHT CHRISTOPH J. , KOCH KARL-MARTIN
Published: April 2021

Passive Heymann nephritis (PHN) in rats is a model of human membranous nephropathy characterized by formation of subepithelial immune deposits in the glomerular capillary wall and complement activation. Oxygen radicals have been implicated in the subsequent glomerular damage which leads to proteinuria. This study examines the involvement of xanthine oxidase in this process. Xanthine oxidase activity was increased nearly twofold in glomeruli isolated 1 and 12 d after induction of PHN, and this was associated with increased glomerular superoxide anion generation. Analysis of glomerular samples by Northern and Western blotting revealed no quantitative changes in xanthine oxidoreductase expression in PHN, suggesting conversion of xanthine dehydrogenase to the oxidase form as the cause of increased activity. Treatment of rats with tungsten, an inhibitor of xanthine oxidase, before induction of PHN resulted in a marked decrease in glomerular xanthine oxidase activity and superoxide anion generation, and decreased proteinuria by 80% (day 12: 423 ± 245 mg/d in PHN versus 78 ± 53 mg/d in tungsten-treated PHN animals, P < 0.01). These findings point to a pivotal role of xanthine oxidase in the pathophysiology of PHN and could be of importance in the therapy of human membranous nephropathy.
α1β1 Integrin-Mediated Collagen Matrix Remodeling by Rat Mesangial Cells Is Differentially Regulated by Transforming Growth Factor-β and Platelet-Derived Growth Factor-BB
Authors: KAGAMI SHOJI , KONDO SHUJI , LÖSTER KLEMENS , REUTTER WERNER , KUHARA TAKASHI , YASUTOMO KOJI , KURODA YASUHIRO
Published: April 2021

Pathologic remodeling of mesangial matrix after glomerular injury is the central biologic feature of glomerular scarring (sclerosis). Transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF)-BB have been implicated in the development of glomerular scarring in rat and human glomerulonephritis. To clarify molecular and cellular mechanisms involved in abnormal mesangial remodeling, this study focused on the role of α1β1 integrin, a collagen/laminin receptor, in rat mesangial cells, using collagen gel contraction as an experimental model of in vivo collagen matrix remodeling and scar formation. In addition, the influence of TGF-β and PDGF-BB on mesangial cell (MC)-mediated collagen gel contraction in association with the α1β1 integrin expression was evaluated. Integrin function blocking studies using anti-α1, β1 subunit antibodies indicated that MC-α1β1 integrin is essentially required not only for collagen-dependent adhesion/migration, but also for gel contraction. Protein synthesis and mRNA analysis experiments demonstrated that TGF-β, but not PDGF-BB, increases the expression of α1β1 integrin in mesangial cells cultured on plastic surface and in collagen gels. The upregulation of α1β1 integrin expression by TGF-β correlated with increases in gel contraction and collagen-dependent adhesion but not migration of mesangial cells. On the other hand, PDGF-BB enhanced MC-mediated gel contraction and migration without affecting cell adhesion to collagen I. Growth factor-induced collagen-dependent adhesion, migration, and gel contraction were significantly attenuated by incubation with anti-α1, β1 subunit antibodies. Thus, these data indicate that α1β1 integrin-mediated collagen matrix remodeling can be modulated by TGF-β and PDGF-BB via different mechanisms. α1β1 integrin-mediated mesangial matrix remodeling induced by TGF-β or PDGF-BB may be a pathogenic mechanism leading to glomerular scarring.
Transforming Growth Factor-β Is a Potent Inhibitor of Extracellular Matrix Degradation by Cultured Human Mesangial Cells
Authors: BARICOS WILLIAM H. , CORTEZ SHIRLEY L. , DEBOISBLANC MICHAEL , XIN SHI
Published: April 2021

Accumulation of the glomerular extracellular matrix (ECM) is a pivotal event in the progression from acute glomerular injury to end-stage renal disease. Although enhanced ECM synthesis has been demonstrated to contribute to ECM accumulation, the role of decreased ECM degradation is largely unknown. It was previously shown that glomerular ECM degradation is mediated by a plasminogen activator (PA)/plasmin/matrix metalloproteinase 2 (MMP-2) cascade. However, little information is available regarding the factors that regulate the activity of this degradative cascade in normal or pathologic states. Transforming growth factor-β1 (TGF-β1) is shown here to be a potent inhibitor of ECM degradation by cultured human mesangial cells. Using human mesangial cells grown on thin films of 125I-labeled Matrigel, dose-dependent inhibition of ECM degradation in the presence of TGF-β1 was observed, reaching >90% inhibition with 0.4 ng/ml TGF-β1. Addition of anti-TGF-β antibodies (4 μg/ml) in the absence of exogenous TGF-β increased ECM degradation (1.8 ± 0.2-fold versus controls, P < 0.05). In contrast, platelet-derived growth factor, at concentrations up to 10 ng/ml, had no effect on ECM degradation. TGF-β completely blocked the conversion of plasminogen to plasmin and markedly reduced the conversion of latent MMP-2 to active MMP-2. TGF-β did not significantly alter the levels of tissue PA, total MMP-2, or tissue inhibitor of metalloproteinase-1, but did increase the levels of PA inhibitor-1 (1.8-fold, P < 0.05), the major physiologic inhibitor of PA. These data document that TGF-β is a potent inhibitor of ECM degradation by cultured human mesangial cells, and they suggest that decreased mesangial matrix degradation, caused by TGF-β-mediated decreases in the activity of the PA/plasmin/MMP-2 cascade, may contribute to the glomerular matrix accumulation that occurs in progressive renal disease.
Resistance to Remnant Nephropathy in the Wistar-Furth Rat
Authors: FITZGIBBON WAYNE R. , GREENE EDDIE L. , GREWAL JASJIT S. , HUTCHISON FLORENCE N. , SELF SALLY E. , LATTEN SAJATA Y. , ULLIAN MICHAEL E.
Published: April 2021

The Wistar-Furth rat, an inbred strain resistant to actions of mineralocorticoids, was used to study the concept that mineralocorticoids contribute to progressive renal injury. It was postulated that if chronic nephropathy depends on aldosterone and if Wistar-Furth rats are resistant to aldosterone, remnant nephropathy would be attenuated in Wistar-Furth rats. Wistar-Furth rats and control Wistar rats were subjected to 5/6 nephrectomy or a sham procedure and then followed for 4 wk. Renal ablation resulted in hypertension at 4 wk in both strains (164 ± 5 [Wistar-Furth] versus 184 ± 7 [Wistar] mmHg mean arterial pressure), with sham animals remaining normotensive (134 ± 6 mmHg). Renal damage in response to 5/6 nephrectomy was greatly decreased in Wistar-Furth rats compared with Wistar rats. Albuminuria was markedly less in Wistar-Furth rats (12.7 ± 4.2 [Wistar-Furth] versus 97.4 ± 22.6 [Wistar] mg/d per 100 g body wt, P < 0.01). Glomerular damage, consisting of mesangial proliferation, mesangial lysis, and segmental necrosis, was observed in 42% of glomeruli from Wistar rats but in 0% of glomeruli from Wistar-Furth rats (P < 0.01). To address the possibility that higher BP in partially nephrectomized Wistar rats mediated the greater renal damage, the study was repeated, with Wistar rats (not Wistar-Furth rats) being treated with a hydralazine-reserpine-hydrochlorothiazide regimen. Although this antihypertensive regimen equalized BP (conscious systolic) (144 ± 8 mmHg [Wistar] versus 157 ± 7 mmHg [Wistar-Furth] at 4 wk), albuminuria remained more than 10-fold greater in Wistar rats. In summary, renal damage upon 5/6 nephrectomy was markedly reduced in Wistar-Furth rats, a finding not attributable to reduced systemic BP. Since Wistar-Furth rats have been shown previously to be resistant to the actions of mineralocorticoids, the data from the present study support the hypothesis that aldosterone mediates, at least in part, the renal injury attendant to renal mass reduction.
Evidence that Microdeletions in the α Globin Gene Protect Against the Development of Sickle Cell Glomerulopathy in Humans
Authors: GUASCH ANTONIO , ZAYAS CARLOS F. , ECKMAN JAMES R. , MURALIDHARAN KASINATHAN , ZHANG WEI , ELSAS LOUIS J.
Published: April 2021

There is a large variability in the severity of the clinical manifestations of sickle cell anemia (SSA), including renal involvement. Haplotypes in the β-globin gene cluster associated with the geographical origin of the sickle mutation, as well as microdeletions in the α-globin genes, could provide an epigenetic influence on the heterogeneous outcome in SSA. It has been determined that the cause of progressive renal insufficiency in SSA is a glomerulopathy, clinically detected by the presence of macroalbuminuria (albumin excretion rate >300 mg/g creatinine). To investigate the role of the α-globin gene microdeletion and β-globin gene cluster haplotypes on the degree of glomerular involvement, 76 adult SSA patients (hemoglobin SS) were studied to determine the relationship between these genetic markers and the development of sickle cell glomerulopathy. Macroalbuminuria was present in 22 (29%) of 76 adult SSA patients. The coinheritance of microdeletions in one or two of the four α-globin genes (α-thalassemia) was associated with a lower prevalence of macroalbuminuria (13%) versus patients with intact α-globin genes (40%, P = 0.01). By contrast, there was no association between albuminuria and β-globin gene haplotypes (Central African Republic [CAR] versus non-CAR haplotypes). Patients with α-globin gene microdeletions had lower mean corpuscular volumes and mean corpuscular hemoglobin concentration than patients with all four α genes (86 ± 2 versus 99 ± 3 fl, and 33.9 ± 0.2 versus 34.9 ± 0.2%, respectively, P < 0.05). There were no such hematologic differences between CAR and non-CAR β-globin haplotypes. There were no differences in duration of disease (age), hemoglobin levels, reticulocyte index, and lactate dehydrogenase levels between those with and without glomerulopathy, but the mean arterial pressure was higher (87 ± 1 mmHg) in patients with intact α gene locus versus those with microdeletions (80 ± 2 mmHg, P < 0.05). It is concluded that the coinheritance of microdeletions in the α-globin gene locus in SSA patients confers “renoprotection” by mechanisms not related to the degree of anemia or the severity of hemolysis, but could be related to a reduced mean corpuscular volume or to a lower erythrocyte hemoglobin concentration.
Management of Bacteremia Associated with Tunneled-Cuffed Hemodialysis Catheters
Authors: BEATHARD GERALD A.
Published: April 2021

The dominant problem associated with the use of tunneled-cuffed catheters is infection. When this occurs, two issues must be addressed: treatment of the infection and management of the catheter. The purpose of this 2-yr study was to report the results of a prospective observational series in which catheter management was based on the clinical picture presented by the patient. Data were collected on patients with catheter-related bacteremia (CRB) dealt with in one of three ways: (1) minimal symptoms with a normal-appearing tunnel and exit site (exchange over guidewire within 48 h of antibiotic initiation [Xchng group], 49 cases); (2) minimal symptoms but with tunnel or exit site infection (exchange over a guidewire with creation of a new tunnel [Nutunl group], 28 cases); and (3) severe clinical symptoms (catheter removal with delayed replacement after defervescence [Delay group], 37 cases). All cases were treated immediately with empiric antibiotics followed by 3 wk of antibiotic therapy based on culture sensitivities. A cure was defined as a 45-d symptom-free interval after antibiotic therapy was complete. A cure rate total of 87.8% for the Xchng group, 75% for the Nutunl group, and 86.5% for the Delay group was seen for the 114 episodes of CRB. It is concluded that in selected patients, catheter exchange over a guidewire within 48 h of antibiotic initiation followed by 3 wk of specific antibiotic therapy is a viable treatment option. Additionally, replacing the catheter in patients presenting with severe symptoms of sepsis as soon as they have defervesced is a reasonable approach to therapy.
Body Composition in Renal Transplant Patients
Authors: VAN DEN HAM EUGÉNIE C.H. , KOOMAN JEROEN P. , CHRISTIAANS MAARTEN H.L. , NIEMAN FRED H.M. , VAN KREEL BERNHARD K. , HEIDENDAL GUIDO A.K. , VAN HOOFF JOHANNES P.
Published: April 2021

Whether multifrequency bioelectrical impedance analysis (MF-BIA), a relatively new method for measuring body composition, is also applicable for accurate body composition measurements in renal transplant (RTx) patients is not known. Therefore, the use of MF-BIA is validated in 77 RTx patients with a stable renal function at least 2 yr posttransplantation. MF-BIA is compared to isotope dilution techniques for measurement of body water compartments, and to dual energy x-ray absorptiometry (DEXA) and anthropometry for measurement of fat and fat free mass. Finally, DEXA and anthropometry are compared to each other. Method agreement is assessed by intraclass correlation coefficients (ICC) and plotted by Bland and Altman analysis. MF-BIA significantly underestimates total body water (TBW, 0.7 ± 2.1 L) and overestimates the extracellular water (ECW, 3.3 ± 1.8 L) compared to isotope dilution; the ICC between both techniques is 0.943 for TBW and 0.846 for ECW. The percentage body fat (BF) measured by MF-BIA is significantly higher than both BF measured by DEXA (3.4 ± 4.7%) or by anthropometry (5.5 ± 5.2%). The ICC between MF-BIA and DEXA is 0.887 and between MF-BIA and anthropometry 0.856. BF measured by DEXA is significantly higher than BF measured by anthropometry (2.1 ± 4.4%); their ICC is 0.913. In conclusion, MF-BIA seems to be suitable for measurement of TBW in RTx patients; however, method agreement between isotope dilution and MF-BIA for the measurement of ECW is not satisfactory. In the assessment of fat and fat free mass, the reliability of MF-BIA appears to be questionable. Method agreement between DEXA and anthropometry seems to be slightly better.
Polyomavirus Infection of Renal Allograft Recipients
Authors: NICKELEIT VOLKER , HIRSCH HANS H. , BINET ISABELLE F. , GUDAT FRED , PRINCE OLIVER , DALQUEN PETER , THIEL GILBERT , MIHATSCH MICHAEL J.
Published: April 2021

Polyomavirus (PV) exceptionally causes a morphologically manifest renal allograft infection. Five such cases were encountered in this study, and were followed between 40 and 330 d during persistent PV renal allograft infection. Transplant (Tx) control groups without PV graft infection were analyzed for comparison. Tissue and urine samples were evaluated by light microscopy, immunohistochemistry, electron microscopy, and PCR. The initial diagnosis of PV infection with the BK strain was made in biopsies 9 ± 2 mo (mean ± SD) post-Tx after prior rejection episodes and rescue therapy with tacrolimus. All subsequent biopsies showed persistent PV infection. Intranuclear viral inclusion bodies in epithelial cells along the entire nephron and the transitional cell layer were histologic hallmarks of infection. Affected tubular cells were enlarged and often necrotic. In two patients, small glomerular crescents were found. In 54% of biopsies, infection was associated with pronounced inflammation, which had features of cellular rejection. All patients were excreting PV-infected cells in the urine. PV infection was associated with 40% graft loss (2 of 5) and a serum creatinine of 484 ± 326 μmol/L (mean ± SD; 11 mo post-Tx). Tx control groups showed PV-infected cells in the urine in 5%. Control subjects had fewer rejection episodes (P < 0.05) and stable graft function (P = 0.01). It is concluded that a manifest renal allograft infection with PV (BK strain) can persist in heavily immunosuppressed patients with recurrent rejection episodes. PV mainly affects tubular cells and causes necrosis, a major reason for functional deterioration. A biopsy is required for diagnosis. Urine cytology can serve as an adjunct diagnostic tool.
Regulation of Thick Ascending Limb Ion Transporter Abundance in Response to Altered Acid/Base Intake
Authors: KIM GHEUN-HO , ECELBARGER CAROLYN , KNEPPER MARK A. , PACKER RANDALL K.
Published: April 2021

Changes in ammonium excretion with acid/base perturbations are dependent on changes in medullary ammonium accumulation mediated by active NH4
+ absorption by the medullary thick ascending limb. To investigate whether alterations in the abundance of medullary thick ascending limb ion transporters, namely the apical Na+/K+(NH4
+)/2Cl--cotransporter (BSC-1), the apical Na+/H+-exchanger (NHE3), and the Na+/K+-ATPase α1-subunit, may be responsible in part for altered medullary ammonium accumulation, semiquantitative immunoblotting studies were performed using homogenates from the inner stripe of the rat renal outer medulla. After 7 d of NH4Cl (7.2 mmol/220 g body wt per d) loading (associated with increased medullary ammonium accumulation), neither BSC-1 nor Na+/K+-ATPase protein expression was altered, but NHE3 protein abundance was significantly increased. On the other hand, both BSC-1 and Na+/K+-ATPase protein abundance was increased significantly in rats fed NaHCO3 (7.2 mmol/220 g body wt per d) for 7 d. Rats fed a high-NaCl diet (7.7 mEq Na+/220 g body wt per d) for 5 d also showed marked increases in both BSC-1 and Na+/K+-ATPase expression. The expression level of NHE3 protein did not change with either NaHCO3 or high NaCl intake. None of these three transporters showed a significant difference in abundance between the groups fed equimolar (7.2 mmol/220 g body wt per d for 7 d) NaHCO3 or NaCl. It is concluded that outer medullary BSC-1 and Na+/K+-ATPase α1-subunit protein abundance is increased by chronic Na+ loading but not by acid/base perturbations and that outer medullary NHE3 protein abundance is increased by chronic NH4Cl loading.
Dual Effect of Nitric Oxide Donors on Cyclooxygenase-2 Expression in Human Mesangial Cells
Authors: DÍAZ-CAZORLA MANUELA , PÉREZ-SALA DOLORES , LAMAS SANTIAGO
Published: April 2021

Nitric oxide (NO) is emerging as a key regulator of gene expression, capable of playing either positive or negative roles. The results of this study indicate that NO exerts a dual effect on cyclooxygenase-2 (COX-2) expression in human mesangial cells (HMC). Treatment of HMC with NO synthase inhibitors attenuated interleukin-1β (IL-1β)/tumor necrosis factor-α (TNF-α)-elicited COX-2 protein and mRNA expression, suggesting a positive role of endogenous NO on COX-2 induction. However, NO donors (sodium nitroprusside [SNP] and S-nitroso-N-acetylpenicillamine [SNAP]) amplified cytokine-elicited COX-2 expression at early time points of treatment (up to 8 h for mRNA and up to 24 h for protein expression), but were inhibitory at later times. Oligonucleotide decoy experiments confirmed the importance of nuclear factor κB (NF-κB) activation for COX-2 induction by IL-1β/TNF-α. Treatment with N
G-nitro-L-arginine methyl ester (L-NAME) did not affect initial activation of NF-κB by IL-1β/TNF-α, but unveiled an inhibitory effect of NO generation on NF-κB activity after 4 h. In HMC supplemented with SNP, cytokine-induced NF-κB activation was potentiated at early times of induction (5 to 15 min), but inhibited at later times (1 to 4 h), suggesting a dual effect of NO donors on NF-κB activation. Interestingly, IκBα protein levels followed a reciprocal pattern of expression: IκBα levels were lower at early times of induction in NO donor-supplemented cells; however, after 1 h of treatment, IκBα levels became higher than in cells treated only with cytokines. In the presence of SNP, cytokine-elicited IκBα mRNA induction was initially delayed, but was amplified at later times. These changes in IκBα expression could contribute to the dual effects of NO donors on NF-κB activation and COX-2 expression in HMC.
Relationship between Kidney Size, Renal Injury, and Renal Impairment Induced by Shock Wave Lithotripsy
Authors: WILLIS LYNN R. , EVAN ANDREW P. , CONNORS BRET A. , BLOMGREN PHIL , FINEBERG NAOMI S. , LINGEMAN JAMES E.
Published: April 2021

The relationship between kidney size and impaired renal function induced by shock-wave lithotripsy (SWL) was examined in 6- and 10-wk-old anesthetized pigs. Each pig received 2000 shock waves, 24 kV, or sham SWL to the lower pole calyx of one kidney. Bilateral GFR, renal plasma flow (RPF), and para-aminohippurate extraction was measured 1 h before and 1 and 4 h after SWL. The kidneys were then removed for morphometric analysis. Mean kidney weights were 66.1 ± 2.7 g (n = 9) and 103.1 ± 3.3 g (n = 8) in the SWL groups, and 60.1 ± 2.6 g (n = 9) and 82.3 ± 4.0 g (n = 9) in the sham-SWL groups. SWL-induced lesions occupied a significantly greater volume of the small kidneys (6.1 ± 1.7 vol % versus 1.5 ± 0.2 vol % in the large kidneys). RPF was significantly reduced by SWL in small and large kidneys, but to a significantly greater extent in small kidneys. RPF was also significantly reduced in the contralateral kidneys of both groups, but only at 1 h after SWL. SWL significantly reduced GFR to similar degrees in both kidneys of both groups, regardless of kidney size. Para-aminohippurate extraction was likewise reduced to similar degrees in both groups, but this effect was evident only in the SWL-treated kidneys, and only in the pole to which the shock waves had been applied. The injury induced by SWL affected a larger fraction of small kidneys than large ones, and the renal vasoconstriction induced by SWL was greatest in small kidneys.
Effect of Increasing Baseline Immunosuppression on the Prevalence of Clinical and Subclinical Rejection
Authors: NICKERSON PETER , JEFFERY JOHN , GOUGH JAMES , GRIMM PAUL , MCKENNA RACHEL , BIRK PATRICIA , RUSH DAVID
Published: April 2021

This group has reported that treatment of subclinical rejection in the first 3 mo posttransplant with corticosteroids decreases late clinical rejections and improves graft function at 2 yr in renal transplant recipients. The current study was performed to determine whether an increase in baseline immunosuppression would decrease the prevalence of early subclinical rejections, as well as the incidence of early and late clinical rejections. Patients received mycophenolate mofetil (MMF) and Neoral cyclosporin A (CsA) posttransplant (n = 29), of which 17 underwent protocol biopsies at months 1, 2, 3, and 6 (Neoral + MMF Protocol Biopsy [Bx]), while 12 declined protocol biopsies (Neoral + MMF Control). These individuals were compared with 72 historical control patients treated with Sandimmune CsA and Imuran, of which 36 had undergone protocol biopsies at months 1, 2, 3, and 6 (Sandimmune + Azathioprine [AZA] Protocol Bx), and 36 had a protocol biopsy at month 6 (Sandimmune + AZA Control). Baseline immunosuppression with Neoral + MMF decreased the incidence of early clinical rejections (0 to 3 mo) and cumulative corticosteroid exposure, but had no impact on the prevalence of early subclinical rejection. Moreover, to maximally decrease the risk of developing late clinical rejections (months 7 to 12) in Neoral + MMF patients required that protocol biopsies be done and that subclinical rejection be treated. The paradoxical finding of recent clinical trials that a reduction in acute clinical rejection has not improved long-term graft outcome may be explained in part by the failure to control subclinical rejection.
The Luminal P2Y Receptor in the Isolated Perfused Mouse Cortical Collecting Duct
Authors: DEETJEN PHILIPP , THOMAS JO[Combining Diaeresis]RG , LEHRMANN HEIKO , KIM SUNG JOON , LEIPZIGER JENS
Published: April 2021

Extracellular nucleotides regulate renal ion transport. With the use of in vitro perfusion and [Ca2+]i imaging, this study investigated whether mouse and rabbit cortical collecting ducts (CCD) respond to luminal nucleotides. In mouse CCD, luminal ATP (EC50: 10 μM) and UTP (EC50: 9.7 μM) increased [Ca2+]i with an initial peak and a plateau. To make certain that basolateral P2 receptors were not activated by luminal nucleotides via leak diffusion, luminal trypsin (1 μM), a known agonist for basolateral proteinase-activated receptors, was perfused. Mouse CCD that were responsive to luminal ATP were nonresponsive to luminal trypsin but always showed [Ca2+]i elevations by basolateral trypsin (10 or 100 nM). Luminal α,β- and β,γ-methylene ATP, 2-methyl-S-ATP, ADP, UDP, and 2′,3′-O-4-benzoylbenzoyl ATP had no effect (100 μM, n = 9). Without external Ca2+, luminal ATP still stimulated a [Ca2+]i increase. Mouse CCD also responded to basolateral ATP (EC50: 23 μM) and UTP (EC50: 23 μM) with smaller [Ca2+]i elevations. Confocal microscopy of perfused CCD showed that luminal ATP (100 μM) rapidly increased [Ca2+]i in nearly all cells (n = 6) and the same cells that responded to luminal ATP responded to basolateral ATP (100 μM). In contrast, rabbit CCD did not respond to luminal ATP/UTP (n = 8) despite ATP's known effect from the basolateral side (EC50: 34 μM). These data indicate the expression of luminal P2Y receptors (probably P2Y2) in principal cells of mouse CCD but not in rabbit CCD.
Inducible Nitric Oxide Synthase Attenuates Endothelium-Dependent Renal Microvascular Vasodilation
Authors: ICHIHARA ATSUHIRO , HAYASHI MATSUHIKO , NAVAR L. GABRIEL , SARUTA TAKAO
Published: April 2021

Previous studies have demonstrated that inducible nitric oxide synthase (iNOS) plays a key pathophysiologic role during sepsis. The present study was designed to delineate the consequences of iNOS activation on renal microvascular function. Male Sprague-Dawley rats were given intraperitoneal injections of lipopolysaccharide (LPS; 4 mg/kg) at 16 h and 4 h before experimentation. Afferent and efferent arteriolar diameters from LPS-treated and control rats were assessed in vitro with the use of the blood perfused juxtamedullary nephron technique. Basal afferent and efferent arteriolar diameters of LPS-treated rats averaged 19.7 ± 0.9 (n = 7) and 18.3 ± 1.0 μm (n = 5), respectively, and were similar to those of control rats (20.8 ± 0.3 [n = 6] and 18.4 ± 0.6 μm [n = 6], respectively). Superfusion with the selective iNOS inhibitor S,S′-(1,3-phenylenebis[1,2-ethanediyl]) bisisothiourea (PBIT), at the doses of 0.01, 0.1, and 1 μM, significantly decreased afferent and efferent arteriolar diameters in a dose-dependent manner, whereas afferent or efferent arteriolar diameters of control rats were not altered in response to the same doses of PBIT. In the second series of experiments, superfusion with 10 μM acetylcholine (ACh) significantly increased afferent and efferent arteriolar diameters of LPS-treated rats by 14.9 ± 1.6% (n = 9) and 6.6 ± 1.1% (n = 6), respectively. The ACh-induced afferent and efferent arteriolar dilator responses were inhibited by superfusion with the nonselective NOS inhibitor N
ω-nitro-L-arginine (100 μM). However, afferent and efferent arteriolar dilator responses to ACh were significantly enhanced during selective iNOS inhibition with 1 μM PBIT (40.1 ± 0.7% and 25.2 ± 1.3%, respectively). These results suggest that activation of iNOS by LPS increases the influence of nitric oxide on afferent and efferent arteriolar tone and impairs endothelium-dependent nitric oxide effects.
Expression of Endothelial Nitric Oxide Synthase in Human Peritoneal Tissue
Authors: ARRIERO MARÍA M. , RODRÍGUEZ-FEO JUAN A. , CELDRÁN ÁNGEL , MIGUEL LOURDES SÁNCHEZ DE , GONZÁLEZ-FERNÁNDEZ FERNANDO , FORTES JOSÉ , REYERO ANA , FRIEYRO OCTAVIO , PINTA JUAN C. DE LA , FRANCO ANGELES , PASTOR CARLOS , CASADO SANTOS , LÓPEZ-FARRÉ ANTONIO
Published: April 2021

Changes in the expression of endothelial nitric oxide synthase (eNOS) in the peritoneum could be involved in the peritoneal dysfunction associated with peritoneal inflammation. Demonstrated recently in bovine endothelial cells was the existence of cytosolic proteins that bind to the 3′-untranslated region (3′-UTR) of eNOS mRNA and could be implicated in eNOS mRNA stabilization. The present work demonstrates that eNOS protein is expressed in human endothelial and mesothelial peritoneal cells. Escherichia coli lipopolysaccharide shortened the half-life of eNOS message, reducing eNOS protein expression in peritoneal mesothelial and endothelial cells. Moreover, under basal conditions, human peritoneal samples expressed cytosolic proteins that bind to the 3′-UTR of eNOS mRNA. The cytosolic proteins that directly bind to 3′-UTR were identified as a 60-kD protein. After incubation of human peritoneal samples with lipopolysaccharide, the binding activity of the cytosolic 60-kD protein increased in a time-dependent manner. Studies are now necessary to determine the involvement of this 60-kD protein in the regulation of eNOS expression in peritoneal cells and particularly its involvement in the peritoneal dysfunction associated with inflammatory reactions.
A Meta-Analysis of Immunosuppression Withdrawal Trials in Renal Transplantation
Authors: KASISKE BERTRAM L. , CHAKKERA HARINI A. , LOUIS THOMAS A. , MA JENNIE Z.
Published: April 2021

Since the publication of previous meta-analyses of cyclosporine (CsA) and prednisone withdrawal in renal transplant recipients, several additional randomized controlled trials with longer follow-up have been reported. Currently, in nine prednisone withdrawal trials (n = 1461), the proportion of patients with acute rejection was increased by 0.14 (95% confidence interval = 0.10 to 0.17, P < 0.001). In nine prednisone withdrawal trials (n = 1899), the relative risk (RR; RR = 1.0 indicates no risk) of graft failure after withdrawal was also increased (RR = 1.40; range, 1.09 to 1.70, P = 0.012). There was no evidence of between-study heterogeneity for either acute rejection or graft failure in the prednisone withdrawal trials by a χ2 test (P > 0.05). In 10 CsA withdrawal trials (n = 1049), the proportion of patients with acute rejection was increased by 0.11 (0.07 to 0.15, P < 0.001). In 12 trials (n = 1151), the RR of graft failure after CsA withdrawal was 1.06 (95% confidence interval, 0.82 to 1.29, P = 0.646), but a χ2 test indicated that there was study heterogeneity. However, there was no evidence of heterogeneity in the six studies (n = 632) with at least 4.0 yr (5.8 ± 1.7) of follow-up (RR = 0.92; range, 0.64 to 1.20, P = 0.569) or in the seven trials (n = 962) published in peer-reviewed journals (RR = 0.95; range, 0.70 to 1.20 P = 0.682). Finally, in three trials (n = 259) that compared CsA and prednisone withdrawal, there was a nonsignificant trend for less graft failure with CsA withdrawal (RR = 0.63; range, 0.08 to 1.16, P = 0.190). Thus, unlike prednisone withdrawal, CsA withdrawal in select patients seems to impart little risk of long-term graft failure.
PTH-Induced Downregulation of the Type IIa Na/Pi-Cotransporter Is Independent of Known Endocytic Motifs
Authors: HERNANDO NATI , FORGO JUTKA , BIBER JU[Combining Diaeresis]RG , MURER HEINI
Published: April 2021

Parathyroid hormone (PTH)-induced inhibition of renal proximal tubular Na/Pi cotransport involves two consecutive steps: endocytosis followed by lysosomal degradation of the type IIa Na/Pi cotransporter. Tyrosine-, dileucine-, and diacidic-based motifs are suggested to be involved in endocytosis and/or lysosomal targeting of different plasma membrane proteins. The rat type IIa cotransporter (NaPi2) contains two cytoplasmic tyrosine residues (Y) within sequences highly homologous to tyrosine-based motifs (GY402FAM and Y509RWF), three cytoplasmic dileucine (LL101, LL374, and LI591) and two cytoplasmic diacidic motifs (EE81 and EE616). We studied the role of these motifs on the PTH-induced retrieval and lysosomal degradation of the NaPi2 cotransporter. To follow its trafficking in vivo, the NaPi2 protein was fused to the carboxyl-terminal end of the enhanced green fluorescence protein. This fusion did not impair the apical targeting or the PTH-induced endocytosis of the wild-type cotransporter when transfected in opossum kidney cells. Single and multiple Y and LL mutants retained the apical targeting and the PTH-induced degradation. Mutations of the diacidic motifs were also without effect. These data suggest that the above three motifs are not required for the PTH-induced internalization and/or degradation of the cotransporter.
Rats Transgenic for Human Renin and Human Angiotensinogen as a Model for Gestational Hypertension
Authors: BOHLENDER JU[Combining Diaeresis]RGEN , GANTEN DETLEV , LUFT FRIEDRICH C.
Published: April 2021

Animal models of gestational hypertension are problematic. A novel mouse model was described earlier. The dams in that study were transgenic for human angiotensinogen and the sires for human renin; human renin was expressed in and produced by the placenta. This model was adapted to the rat, which has greater utility in terms of chronic instrumentation and physiologic measurements. Female rats transgenic for human angiotensinogen were mated with rats transgenic for human renin. Telemetry BP increased on day 5 of pregnancy from 110/80 mmHg to as high as 180/140 mmHg, while heart rate increased slightly. The renin transgene was expressed in the placenta, which resulted in increased human plasma renin concentration from 0 to 937 ± 800 ng angiotensin I ml/h; the values returned to 0 after delivery. Female rats transgenic for human renin that were mated with male rats transgenic for human angiotensinogen in contrast exhibited a decrease in BP. In these rats, human angiotensinogen in plasma remained undetectable. Double transgenic offspring of these transgenic rats developed hypertension and end-organ damage, regardless of the source of the transgenes. The conclusion is that transgenic rats that bear human renin and angiotensinogen genes make an attractive model for gestational hypertension. The rat model will have greater utility than the mouse model.
Interleukin-4 and Interleukin- 13 Act on Glomerular Visceral Epithelial Cells
Authors: VAN DEN BERG JOSÉ G. , ATEN JAN , CHAND M. ANWAR , CLAESSEN NIKE , DIJKINK LISETTE , WIJDENES JOHN , LAKKIS FADI G. , WEENING JAN J.
Published: April 2021

In minimal change nephrosis (MCN), proteinuria is associated with structural changes of the glomerular visceral epithelial cells (GVEC). The occurrence of MCN has been associated with T-helper2 lymphocyte-dependent conditions. To examine a direct role for type 2 cytokines in GVEC injury, the expression of interleukin (IL)-4/IL-13 receptors by GVEC and direct effects of IL-4 and IL-13 on GVEC were studied. Reverse transcription-PCR showed that isolated human and rat glomeruli and cultured human and rat GVEC expressed mRNA for IL-4Rα, IL-13Rα1, and IL-13Rα2. Protein expression of IL-4Rα and IL-13Rα2 by GVEC in human kidney biopsies and by cultured human GVEC was detected by immunohistochemistry. Western blotting demonstrated phosphorylation of STAT6 in cultured GVEC upon incubation with IL-4 or IL-13. This indicated signal transduction via the heterodimeric receptor complex IL-4R2, which is composed of the IL-4Rα and the IL-13Rα1. Direct effects on GVEC function were examined in monolayer experiments. IL-4 and IL-13 dose-dependently decreased transepithelial electrical resistance of monolayers of rat GVEC to approximately 30 and 40% of baseline values, respectively. The transepithelial electrical resistance decrease was associated with a significant increase in short-circuit current, whereas no changes were observed in the transmonolayer flux of the macromolecules horseradish peroxidase (molecular weight, 44 kD) and 14C-mannitol (molecular weight, 182 Da). No changes in cell structure were observed with electron microscopy. It is concluded that by binding to specific IL-4/IL-13 receptors, IL-4 and IL-13 can exert specific effects on GVEC function, which could be of pathogenetic relevance for glomerular injury in MCN.
Time Dependency of Factors Affecting Renal Allograft Survival
Authors: PROMMOOL SURAZEE , JHANGRI GIAN S. , COCKFIELD SANDRA M. , HALLORAN PHILIP F.
Published: April 2021

The function of renal transplants can deteriorate at any time posttransplant, but the risks and mechanisms may differ at different times posttransplant. Survival of 522 consecutive cadaveric renal transplant recipients followed for at least 6 mo were analyzed, with patient death censored. The overall risk factors in univariate analysis were acute rejection requiring antibody therapy (AR), delayed graft function, elevated serum creatinine at 6 mo, high panel-reactive antibodies, and donor age ≥55 yr, with borderline effects of recipient age and female gender. These risks were studied in each of three intervals posttransplantation: ≤6 mo, 6 mo to 5 yr, and >5 yr. Of the 135 graft failures, 53 occurred ≤6 mo, 61 between 6 mo and 5 yr, and 21 beyond 5 yr. By multivariate analysis, the risks for graft failure in interval ≤6 mo were AR (hazard ratio (HR) = 4.86, P < 0.001); delayed graft function (HR = 1.47, P = 0.06); and high panel-reactive antibodies (HR = 2.04, P = 0.03). Between 6 mo and 5 yr, the risks for graft loss were AR (HR = 2.87, P < 0.001) and serum creatinine at 6 mo ≥150 μmol/L (HR = 3.69, P < 0.001). Beyond 5 yr the risk factors were donor age ≥55 yr (HR = 5.87, P = 0.002), with a borderline effect of kidneys from female donors (HR = 2.28, P = 0.07). HLA-A, -B, and -DR matching and presensitization had most of their effect through early AR and impaired function. The results indicate that risks for graft loss are time-dependent: early losses correlate with injury and rejection, but late events correlate with donor age and possibly workload.
Developing A Process Parameter Based Performance Monitoring and Evaluation System for Power Plant
Authors: BULUT Mehmet
Published: April 2021

Today, there are many electricity production methods. Thermal power plants are still widely used for electricity production from hydrocarbon sources as one of the electricity generation options. Due to their complex structure, thermal power plants are composed of sections that interact with each other, and they are called units. A change in the performance of any unit or equipment affects the operation of the entire plant positively or negatively. Therefore, performance monitoring and evaluation systems are designed to support the measurement and monitoring of the performance of plant and equipment. In order to increase the availability of the plant, equipment-based maintenance plans should be prepared according to the maintenance needs of the equipment. In this study, a power plant performance monitoring and evaluation system has been developed and designed using process parameters approach for the parameters affecting the performance of the plant. In order to monitor and evaluate the performance of thermal power plants, the requirements of the system were revealed and the efficiency and performance increases to be achieved by designing and using this system specific to a natural gas power plant were examined and results are given.
Sentiment Classification Performance Analysis Based on Glove Word Embedding
Authors: KIRELLİ Yasin , ÖZDEMİR Şebnem
Published: April 2021

Representation of words in mathematical expressions is an essential issue in natural language processing. In this study, data sets in different categories are classified as positive or negative according to their content. Using the Glove (Global Vector for Word Representation) method, which is one of the word embedding methods, the effect of the vector set based on the word similarities previously calculated on the classification performance has been analyzed. In this study, the effect of pretrained, embedded and deterministic word embedding classification performance has analyzed by using Long Short Term Memory (LSTM). The porposed LSTM based deep learning model has been tested on three different data sets and the results was evaluated.
CFD Investigation of Different Flow Field Designs for Efficient PEMFC Performance
Authors: ÖZDEMİR Safiye Nur , TAYMAZ İmdat
Published: April 2021

Proton exchange membrane (PEM) fuel cell performance depends substantially on the geometry, configuration of the flow channels, and size. A right gas flow field pattern requires a homogeneous reactant distribution, low-pressure drop, and good water management. This paper outlines a numerical study, investigated the influence of the U-type, Z-type, and serpentine flow field configuration on the steady-state cell performance using the CFD technique ANSYS FLUENT PEMFC module. The main goal of this study focuses on a novel perspective for enhancing the design of the PEMFC resulting in better performance. The results indicate that the PEMFC with serpentine flow field configuration yields a significantly higher power density compared to the other designs.
Model Solutions and Pragmatism in Developing ICT for Public Consultations
Authors: Przybylska Anna
Published: April 2021

The focus of this article is on the process of developing the inDialogue software within the loop of communication between researchers and the clerks who organize public consultations in local governments. The software was created in response to problems diagnosed during studies on the quality of public consultations in Poland. The design supports transparent, thoughtful, and collaborative planning for public consultations in town or city halls, in order to create an environment conducive to informed and inclusive opinion formation among citizens. Within the project, a pragmatic approach means some degree of openness among researchers and designers in negotiating the features of the software with institutional users. Testing inDialogue in nine municipalities, we asked the following questions 1) How do the clerks respond to the model of public consultations that inDialogue implements? and 2) How do they build a relationship with a project that intervenes in their routines? Analysis of the data from the evaluation questionnaires shows that although, overall, the clerks gave the highest rating for the software’s ability to introduce order into the process of public consultations, they often complained that the features behind the structuration effect were time-consuming. Depending on the city or town hall, more weight was given to one or another aspect of the tradeoff. No less important for the institutionalization of deliberative public consultations is the controversy over registration and verification, and consequently, the recruitment of participants. In the article, this is discussed in the context of the ambiguities in the law, and the different values that the various local governments attribute to participation. Moreover, the study demonstrated that prior experience in public consultations combined with an openness to experimenting, a repertoire of skills in communication and data analysis, a motivation to join the project, the length and depth of collaboration with researchers, and the direct involvement of a decision maker all affected clerks’ comprehension and acceptance of the use of inDialogue.
Just Adapt: Engaging Disadvantaged Young People in Planning for Climate Adaptation
Authors: Davies Anna R. , Hügel Stephan
Published: April 2021

The visibility of young people in climate change debates has risen significantly since the inception of the Fridays for Future movement, but little is known about the diversity of positions, perspectives and experiences of young people in Ireland, especially with respect to climate change adaptation planning. To close this knowledge gap, this article first interrogates key emergent spaces of public participation within the arena of climate action in Ireland in order to identify the extent of young people’s participation and whether any specific consideration is given to disadvantaged groups. It then tests the impacts of workshops specifically designed to support disadvantaged young people’s engagement with climate change adaptation which were rolled out with a designated Delivering Equality of Opportunity in Schools school in inner-city Dublin, Ireland. We found limited attention to public participation in climate change adaptation planning generally, with even less consideration given to engaging young people from disadvantaged communities. However, positive impacts with respect to enhanced knowledge of climate change science and policy processes emerged following participation in the workshops, providing the bedrock for a greater sense of self-efficacy around future engagement with climate action amongst the young people involved. We conclude that what is needed to help ensure procedural justice around climate action in Ireland are specific, relevant and interactive educational interventions on the issue of climate change adaptation; interventions which are sensitive to matters of place and difference.
Ground-Motion Intensity Measure Correlations on Interface and Intraslab Subduction Zone Earthquakes Using the NGA-Sub Database
Authors: Macedo Jorge , Liu Chenying
Published: April 2021

The NGA-Sub (subduction zone earthquake) database developed by the Pacific Earthquake Engineering Research center is used to derive new correlation coefficients for a number of ground-motion intensity measure (IM) parameters from ground motions in subduction zone earthquakes, considering both interface and intraslab tectonic settings. The IMs include peak ground acceleration, pseudospectral accelerations with periods from 0.01 to 10 s, Arias intensity, cumulative absolute velocity, peak ground velocity, and significant duration. Comparisons of the estimated correlation coefficients for ground motions from the interface and intraslab tectonic settings generally show a good agreement. Our estimations are also in good agreement with correlation coefficients estimated in previous studies that used ground motions from shallow crustal earthquakes, supporting the concept that any variation in correlation coefficients comes from spectral shape (i.e., the distribution of peaks and troughs) rather than tectonic region. This study also explores the influence of parameters such as magnitude, distance, and site conditions on the estimated correlation coefficients. We did not find apparent trends of the correlation coefficients with respect to these parameters. Finally, we propose analytical models to estimate correlation coefficients between the IMs explored in this study, considering both subduction interface and intraslab tectonic settings.