bluuebunny/crossref_metadata_2025_split huggingface dataset:
Posttransplantation Relapse of FSGS Is Characterized by Glomerular Epithelial Cell Transdifferentiation
Authors: BARIÉTY JEAN , BRUNEVAL PATRICK , HILL GARY , IRINOPOULOU THEANO , MANDET CHANTAL , MEYRIER ALAIN 
Published: April 2021

Abstract.
This study examined six cases of idiopathic nephrotic syndrome with primary lesions of focal segmental glomerulosclerosis (FSGS) that relapsed after renal transplantation. The glomerular lesions comprised the cellular, the collapsing, and the scar variants of FSGS and showed shedding of large round cells into Bowman's space and within the tubular lumens. Immunohistochemistry and confocal laser microscopy carried out on kidneys with FSGS relapse disclosed several phenomena. (1) Some podocytes that expressed podocalyxin, synaptopodin, and glomerular epithelial protein-1 were detached from the tuft and were free in the urinary space. (2) In the cellular variant, most podocytes had lost podocyte-specific epitopes (podocalyxin, synaptopodin, glomerular epithelial protein-1, Wilm's tumor protein-1, complement receptor-1, and vimentin). In the scar variant, these podocyte markers were absent from cobblestone-like epithelial cells and from pseudotubules. (3) Podocytes had acquired expression of various cytokeratins (CK; identified by the AE1/AE3, C2562, CK22, and AEL-KS2 monoclonal antibodies) that were not found in the podocytes of control glomeruli. Parietal epithelial cells expressed AE1/AE3 CK that were faintly, if ever, found on the parietal epithelial cells of normal glomeruli. (4) Numerous cells located at the periphery of the tuft or free in Bowman's space and within tubular lumens expressed macrophagic epitopes (identified by PGM1 [CD68], HAM56, and 25F9 monoclonal antibodies). These macrophage-like cells expressed the activation epitopes HLA-DR and CD16. (5) A number of these cells coexpressed podocalyxin + AE1/AE3 CK, podocalyxin + CD68, and CD68 + AE1/AE3. These findings suggest that in primary FSGS relapsing on transplanted kidneys, some “dysregulated” podocytes, occasionally some parietal epithelial cells, and possibly some tubular epithelial cells undergo a process of transdifferentiation. This process of transdifferentiation was especially striking in podocytes that acquired macrophagic and CK epitopes that are absent from normal adult and fetal podocytes.
Renal Interstitial Fibrosis Is Reduced in Angiotensin II Type 1a Receptor-Deficient Mice
Authors: SATOH MINORU , KASHIHARA NAOKI , YAMASAKI YASUSHI , MARUYAMA KEISUKE , OKAMOTO KAZUNORI , MAESHIMA YOUHEI , SUGIYAMA HITOSHI , SUGAYA TAKESHI , MURAKAMI KAZUO , MAKINO HIROFUMI 
Published: April 2021

Abstract.
Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the affected kidney by stimulating the renin-angiotensin system. This study established a UUO model in angiotensin type 1a receptor (AT1a) deficient (mutant) mice to elucidate the role of angiotensin II through AT1a on the fibrosis of the obstructed kidney (OBK). The relative volume of the tubulointerstitium was measured by an image analyzer; deposition of collagen types III and IV and monocyte/macrophage infiltration were histologically examined using specific antibodies. Also determined were the mRNA levels of transforming growth factor-β by Northern blot analysis. Nuclear factor-κB activity was assessed by gel shift assay. UUO in wild mice resulted in a marked expansion of relative volume of the tubulointerstitium, together with increased deposition of collagen types III and IV and number of infiltrated monocytes/macrophages in the interstitium, relative to sham-operated mice. In comparison, these changes were significantly lower in mutant mice with UUO. The mRNA level of transforming growth factor-β was significantly higher in the OBK of wild mice with UUO compared with sham-operated mice. In contrast, the increase in mRNA level in the OBK of mutant mice was significantly less than in wild mice. Finally, UUO resulted in activation of nuclear factor-κB in wild mice but was inhibited in the OBK of mutant mice. The results provide direct evidence that angiotensin II acting via the AT1a plays a pivotal role in the development of tubulointerstitial fibrosis in UUO.
Impact of Dialysis Adequacy on the Mortality and Morbidity of Anuric Chinese Patients Receiving Continuous Ambulatory Peritoneal Dialysis
Authors: SZETO CHEUK-CHUN , WONG TERESA YUK-HWA , CHOW KAI-MING , LEUNG CHI-BON , LAW MAN-CHING , WANG ANGELA YEE-MOON , LUI SIU-FAI , LI PHILIP KAM-TAO 
Published: April 2021

Abstract.
Dialysis adequacy has a major impact on the outcome of continuous ambulatory peritoneal dialysis (CAPD) patients. However, most studies on peritoneal dialysis adequacy have focused on patients with significant residual renal function. The present study examined the effect of dialysis adequacy on anuric CAPD patients. A single-center prospective observational study on 140 anuric CAPD patients was performed. These patients were followed for 22.0 ± 11.9 mo. Dialysis adequacy and nutritional indices, including Kt/V, creatinine clearance (CCr), protein equivalent nitrogen appearance, percentage of lean body mass, and serum albumin level were monitored. Clinical outcomes included actuarial patient survival, technique survival, and duration of hospitalization. In the study population, 64 were male, 36 (25.7%) were diabetic, and 59 (42.1%) were treated with 6 L exchanges per day. The body weight was 59.2 ± 10.2 kg. Average Kt/V was 1.72 ± 0.31, and CCr was 43.7 ± 11.5 L/wk per 1.73m2. Two-yr patient survival was 68.8%, and technique survival was 61.4%. Multivariate analysis showed that DM, duration of dialysis before enrollment, serum albumin, and index of dialysis adequacy (Kt/V or CCr) were independent factors of both patient survival and technique survival. It was estimated that for two patients who differed only in weekly Kt/V, a 0.1 higher value was associated with a 6% decrease in the RR of death (P < 0.05; 95% confidence interval, 0.92 to 0.99). Serum albumin and CCr were the only independent factors that predicted hospitalization. It was found that even when there is no residual renal function, higher dialysis dosage is associated with better actuarial patient survival, better technique survival, and shorter hospitalization. Dialysis adequacy has a significant impact on the clinical outcome of CAPD patients, and the beneficial effect is preserved in anuric patients as well as in an ethnic group that has a low overall mortality.
L-Arginine Supplementation Improves Function and Reduces Inflammation in Renal Allografts
Authors: VOS INGRID H. C. , RABELINK TON J. , DORLAND BERT , LOOS REMKO , MIDDELAAR BEN VAN , GRO[Combining Diaeresis]NE HERMANN-JOSEF , JOLES JAAP A. 
Published: April 2021

Abstract.
Recovery from ischemia/reperfusion and immune-mediated injury in the renal transplant is associated with reduced renal hemodynamics and increased leukocyte infiltration. In diverse models of renal failure, L-arginine supplementation improved hemodynamics and reduced inflammation. However in a proinflammatory environment, L-arginine can worsen renal injury. This study investigated the therapeutic potential of L-arginine supplementation in allogeneic renal transplantation: Brown Norway rat kidneys were transplanted into Lewis rat recipients, with one native kidney remaining. Recipients received low-dose cyclosporin A (2.5 mg/kg per d subcutaneously) to obtain moderate vascular and interstitial rejection, with or without 1% L-arginine in drinking water for 7 d posttransplantation. Transplantation increased renal vasoconstriction (from 16.9 ± 1.33 to 35.1 ± 8.6 units; P < 0.01), thereby reducing GFR (from 0.96 ± 0.09 to 0.48 ± 0.10 ml/min; P < 0.05). Treatment with L-arginine restored renal graft function to levels found in normal donors (renal vascular resistance, 15.7 ± 1.69 units; GFR, 0.80 ± 0.06 ml/min). L-arginine significantly reduced vascular occlusion because of less inflammation, endothelial disruption, and thrombosis. L-arginine also decreased tubulitis, interstitial injury, and macrophage infiltration. These protective effects suggest that L-arginine might be useful as additive therapy to conventional immune suppression.
Oxidized LDL Suppresses NF-κB and Overcomes Protection from Apoptosis in Activated Endothelial Cells
Authors: HEERMEIER KATHRIN , LEICHT WOLFGANG , PALMETSHOFER ALOIS , ULLRICH MARKUS , WANNER CHRISTOPH , GALLE JAN 
Published: April 2021

Abstract.
Atherosclerosis is a chronic inflammatory disease associated with enhanced apoptotic cell death in vascular cells, partly induced by oxidized low-density lipoprotein (OxLDL). However, proinflammatory stimuli such as lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α) activate endothelial cells (EC) and inhibit apoptosis through induction of nuclear factor κB (NF-κB)-dependent genes. This study therefore investigated whether OxLDL or its component, lysophosphatidylcholine (LPC), interacts with the effect of LPS or TNF-α on cell survival. Human EC were incubated with LPS, TNF-α, OxLDL, or LPC alone or in combinations. OxLDL (100 to 200 μg/ml) and LPC (100 to 300 μM) induced apoptosis dose-dependently. LPS and TNF-α had no effect on cell survival in the presence or absence of OxLDL or LPC. LPS and TNF-α both induced the antiapoptotic gene A20, whereas OxLDL and LPC suppressed its induction. Expression of A20 is regulated by NF-κB. OxLDL and LPC dose-dependently suppressed NF-κB activity. For functional analysis, bovine EC were transfected with A20 encoding expression constructs in sense and antisense orientation. Bovine EC that overexpressed A20 were protected against OxLDL-induced apoptosis, whereas expression of antisense A20 rendered cells more sensitive to OxLDL. These results suggest that OxLDL not only induces cell death, as has been shown before, but also compromises antiapoptotic protection of activated EC. OxLDL sensitizes EC to apoptotic triggers by interfering with the induction of A20 during the inflammatory response seen in atherosclerotic lesions. This inhibition is based on repression of NF-κB activation. The effect may be caused by the OxLDL component LPC.
Galectin-3 Modulates Ureteric Bud Branching in Organ Culture of the Developing Mouse Kidney
Authors: BULLOCK SIMON L. , JOHNSON TANYA M. , BAO QI , HUGHES R. COLIN , WINYARD PAUL J. D. , WOOLF ADRIAN S. 
Published: April 2021

Abstract.
Galectin-3 is a mammalian β-galactoside—specific lectin with functions in cell growth, adhesion, and neoplastic transformation. On the basis of expression patterns in humans, it is proposed that galectin-3 modulates fetal collecting duct growth. This article provides evidence that galectin-3 can modulate branching morphogenesis of the mouse ureteric bud/collecting duct lineage. With the use of immunohistochemistry, galectin-3 was not detected in early metanephrogenesis but was upregulated later in fetal kidney maturation when the protein was prominent in basal domains of medullary collecting ducts. Addition of galectin-3 to embryonic days 11 and 12 whole metanephric cultures inhibited ureteric bud branching, whereas galectin-1 did not perturb morphogenesis, nor did a galectin-3 mutant lacking wild-type high-affinity binding to extended oligosaccharides. Exogenous galectin-3 retarded conversion of renal mesenchyme to nephrons in whole metanephric explants but did not affect nephron induction by spinal cord in isolated renal mesenchymes. Finally, addition of a blocking antiserum to galectin-3 caused dilation and distortion of developing epithelia in embryonic day 12 metanephroi cultured for 1 wk. The upregulation of galectin-3 protein during kidney maturation, predominantly at sites where it could mediate cell/matrix interactions, seems to modulate growth of the ureteric tree.
Collecting Duct Is a Site of Sodium Retention in PAN Nephrosis
Authors: DESCHE[Combining Circumflex Accent]NES GEORGES , WITTNER MONIKA , STEFANO ANTONIO DI , JOUNIER SYLVIE , DOUCET ALAIN 
Published: April 2021

Abstract.
Micropuncture studies of the distal nephron and measurements of Na,K-ATPase activity in microdissected collecting tubules have suggested that renal retention of sodium in puromycin aminonucleoside (PAN) nephrotic rats originates in the collecting duct. The present study demonstrated this hypothesis by in vitro microperfusion and showed that amiloride was able to restore sodium balance. Indeed, isolated perfused cortical collecting ducts from PAN-treated rats exhibited an abnormally high transepithelial sodium reabsorption that was abolished by amiloride, and in vivo administration of amiloride fully prevented decreased urinary sodium excretion and positive sodium balance in nephrotic rats. As expected from the aldosterone independence of Na+ retention in PAN nephrotic rats, blockade of aldosterone receptor by potassium canrenoate did not alter urinary Na+ excretion, Na+ balance, or ascites formation in PAN nephrotic rats.
Verocytotoxin-Induced Apoptosis of Human Microvascular Endothelial Cells
Authors: PIJPERS ANTONETTA H. J. M. , SETTEN PETRA A. VAN , HEUVEL LAMBERTUS P. W. J. VAN DEN , ASSMANN KAREL J. M. , DIJKMAN HENDRIKUS B. P. M. , PENNINGS ARIE H. M. , MONNENS LEO A. H. , HINSBERGH VICTOR W. M. VAN 
Published: April 2021

Abstract.
The pathogenesis of the epidemic form of hemolytic uremic syndrome is characterized by endothelial cell damage. In this study, the role of apoptosis in verocytotoxin (VT)-mediated endothelial cell death in human glomerular microvascular endothelial cells (GMVEC), human umbilical vein endothelial cells, and foreskin microvascular endothelial cells (FMVEC) was investigated. VT induced apoptosis in GMVEC and human umbilical vein endothelial cells when the cells were prestimulated with the inflammatory mediator tumor necrosis factor-α (TNF-α). FMVEC displayed strong binding of VT and high susceptibility to VT under basal conditions, which made them suitable for the study of VT-induced apoptosis without TNF-α interference. On the basis of functional (flow cytometry and immunofluorescence microscopy using FITC-conjugated annexin V and propidium iodide), morphologic (transmission electron microscopy), and molecular (agarose gel electrophoresis of cellular DNA fragments) criteria, it was documented that VT induced programmed cell death in microvascular endothelial cells in a dose- and time-dependent manner. Furthermore, whereas partial inhibition of protein synthesis by VT was associated with a considerable number of apoptotic cells, comparable inhibition of protein synthesis by cycloheximide was not. This suggests that additional pathways, independent of protein synthesis inhibition, may be involved in VT-mediated apoptosis in microvascular endothelial cells. Specific inhibition of caspases by Ac-Asp-Glu-Val-Asp-CHO, but not by Ac-Tyr-Val-Ala-Asp-CHO, was accompanied by inhibition of VT-induced apoptosis in FMVEC and TNF-α-treated GMVEC. These data indicate that VT can induce apoptosis in human microvascular endothelial cells.
Effects of Losartan and Amlodipine on Intrarenal Hemodynamics and TGF-β1 Plasma Levels in a Crossover Trial in Renal Transplant Recipients
Authors: IN[Combining Tilde]IGO PABLO , CAMPISTOL JOSEP M. , LARIO SERGIO , PIERA CARLOS , CAMPOS BEGON[Combining Tilde]A , BESCÓS MÓNICA , OPPENHEIMER FEDERICO , RIVERA FRANCISCA 
Published: April 2021

Abstract.
Hypertension and hyperfiltration are two important risk factors for the development of chronic allograft nephropathy. Transforming growth factor-β1 (TGF-β1) is the main cytokine involved in the fibrotic process that is involved in chronic rejection. Angiotensin II upregulates TGF-β1 production. Angiotensin II receptor antagonists therefore could not only control BP but also reduce TGF-β1 production in renal transplant patients. The aim of this study was to compare the effects of losartan and amlodipine on renal hemodynamics, as well as TGF-β1 and endothelin-1 (ET-1) plasma levels in a group of renal transplant patients who had normal renal function and who were treated with cyclosporine. Seventeen renal transplant patients who were receiving cyclosporine and who had normal graft function were included in a random 2 × 2 crossover trial with amlodipine and losartan (6 wk with each therapy). Three studies were performed (at baseline and at the end of both treatment periods) to determine renal hemodynamics, TGF-β1, and ET-1. Both treatments controlled BP to a similar degree, but only amlodipine increased GFR through an increase in the estimated glomerular hydrostatic pressure and filtration fraction. In contrast, losartan maintained GFR and reduced estimated glomerular hydrostatic pressure and filtration fraction significantly. Losartan and amlodipine had opposite effects on TGF-β1. Amlodipine did not affect TGF-β1 concentrations. In contrast, losartan reduced the plasma levels of TGF-β1 by approximately by 50% (from baseline, 5.2 to 2.6 ng/ml; P = 0.01); the majority of the patients reached normal levels of TGF-β1. ET-1 concentrations were significantly higher during amlodipine compared with losartan treatment. The present study documents that with similar control of BP, losartan and amlodipine have opposite effects on renal hemodynamics and on TGF-β1 concentrations. These differences could be important for the management of chronic allograft nephropathy.
Diabetes Insipidus in Uricase-Deficient Mice: A Model for Evaluating Therapy with Poly(Ethylene Glycol)-Modified Uricase
Authors: KELLY SUSAN J. , DELNOMDEDIEU MARIELLE , OLIVERIO MICHAEL I. , WILLIAMS DAVID L. , SAIFER MARK G. P. , SHERMAN MERRY R. , COFFMAN THOMAS M. , JOHNSON ALLAN G. , HERSHFIELD MICHAEL S. 
Published: April 2021

Abstract.
Uricase-deficient mice develop uric acid nephropathy, with high mortality rates before weaning. Urate excretion was quantitated and renal function was better defined in this study, to facilitate the use of these mice as a model for evaluating poly(ethylene glycol)-modified recombinant mammalian uricases (PEG-uricase) as a potential therapy for gout and uric acid nephropathy. The uric acid/creatinine ratio in the urine of uricase-deficient mice ranges from 10 to >30; on a weight basis, these mice excrete 20- to 40-fold more urate than do human subjects. These mice consistently develop a severe defect in renal concentrating ability, resulting in an approximately sixfold greater urine volume and a fivefold greater fluid requirement, compared with normal mice. This nephrogenic diabetes insipidus leads to dehydration and death of nursing mice but, with adequate water replacement, high urine flow protects adults from progressive renal damage. Treatment of uricase-deficient mice with PEG-uricase markedly reduced urate levels and, when initiated before weaning, preserved the renal architecture (as evaluated by magnetic resonance micros-copy) and prevented the loss of renal concentrating function. PEG-uricase was far more effective and less immunogenic than unmodified uricase. Retention of uricase in most mammals and its loss in humans and some other primates may reflect the evolution of renal function under different environmental conditions. PEG-uricase could provide an effective therapy for uric acid nephropathy and refractory gout in human patients.
Chemokine and Chemokine Receptor Expression during Initiation and Resolution of Immune Complex Glomerulonephritis
Authors: ANDERS HANS-JOACHIM , VIELHAUER VOLKER , KRETZLER MATTHIAS , COHEN CLEMENS D. , SEGERER STEPHAN , LUCKOW BRUNO , WELLER LARS , GRÖNE HERMANN-JOSEF , SCHLÖNDORFF DETLEF 
Published: April 2021

Abstract.
Chemokines participate in leukocyte infiltration, which plays a major role in glomerular injury during immune complex glomerulonephritis (IC-GN). Because target cell expression of chemokine receptors (CCR) is thought to mediate leukocyte migration, the expression pattern of chemokines and CCR in a model of IC-GN was examined. The transient course and predominant glomerular pathology of this model allows the examination of both the induction and resolution phases of IC-GN. GN was induced in mice by daily apoferritin injection for 2 wk. Urine samples and kidneys were obtained at 1, 2, and 4 wk. Albuminuria was noted at 2 wk, but resolved after 4 wk. This was associated with glomerular IC deposits and mesangial proliferation. Glomerular macrophage infiltration was prominent at 1 and 2 wk, which resolved at 4 wk. Expression of monocyte chemoattractant protein-1 (MCP-1) and RANTES mRNA was upregulated at week 1 and decreased to control levels at weeks 2 and 4. The expression was localized to glomeruli by in situ hybridization and immunohistochemistry. The mRNA of CCR1, CCR2, and CCR5 but not CCR3 or CCR4 were upregulated at week 1 and decreased at weeks 2 and 4. Expression of CCR5 was located to the glomerulus by in situ hybridization and quantitative reverse transcription-PCR of isolated glomeruli. In summary, in a model of transient IC-GN, MCP-1 and RANTES and their receptors CCR1, CCR2, and CCR5 are expressed early and are already downregulated at the peak of proteinuria and leukocyte infiltration. Resolution of glomerulonephritis is associated with a return to baseline of chemokine and CCR expression. Therefore, it is concluded that glomerular MCP-1 and RANTES production directs circulating leukocytes that express CCR1, CCR2, and CCR5 into the glomerulus. After initiating GN, MCP-1 and RANTES and their receptors are readily downregulated.
Blocking Angiotensin II Synthesis/Activity Preserves Glomerular Nephrin in Rats with Severe Nephrosis
Authors: BENIGNI ARIELA , TOMASONI SUSANNA , GAGLIARDINI ELENA , ZOJA CARLA , GRUNKEMEYER JAMES A. , KALLURI RAGHU , REMUZZI GIUSEPPE 
Published: April 2021

Abstract.
Angiotensin-converting enzyme inhibitors restore size-selective dysfunction of the glomerular barrier in experimental animals and humans with proteinuric nephropathies, although the structural and molecular determinants of such an effect are not completely understood. This study used an accelerated model of experimental nephrosis to assess nephrin gene and protein expression in the kidney and the possible modulating effect of drugs that block angiotensin II (AII) synthesis/activity. Passive Heymann nephritis (PHN) and control animals were studied at day 7, month 4, and month 8. Additional PHN rats were treated with lisinopril or AII receptor blocker L-158,809 and studied at 8 mo. Lisinopril and L-158,809 controlled BP, prevented proteinuria, and protected PHN animals from renal injury. An intense signal of nephrin mRNA was detected in glomeruli of control animals mainly restricted to podocytes. In PHN rats, nephrin staining progressively and remarkably decreased with time. Lisinopril and L-158,809 fully prevented the decrease in nephrin transcripts to levels comparable to those of control rats. Consistent with nephrin mRNA expression, immunostaining of the protein showed a progressive decrease in kidneys from PHN rats that was completely abolished by lisinopril and L-158,809. In summary, progressive renal injury was associated with downregulation of nephrin gene that was totally prevented by angiotensin-converting enzyme inhibitor and AII receptor blocker, suggesting that renoprotection afforded by drugs that interfere with AII synthesis/activity was related to an effect on nephrin assembly.