bluuebunny/crossref_metadata_2025_split huggingface dataset:
Urinary Protein Binding Does Not Affect Response to Furosemide in Patients with Nephrotic Syndrome
Authors: AGARWAL RAJIV , GORSKI J. CHRISTOPHER , SUNDBLAD KIMBERLY , BRATER D. CRAIG 
Published: April 2021

Abstract.
Response to loop diuretics in patients with nephrotic syndrome (NS) is subnormal. Studies in animal models of NS have suggested that binding of diuretic to urinary albumin is one of the mechanisms that may be operative in this diuretic resistance. To explore this hypothesis, 12 patients with NS were studied to determine whether displacement from urinary protein binding with sulfisoxazole would restore response to 120 mg of furosemide. The study was stopped after treating seven patients because it was clear that sulfizoxazole had no effect. Sodium excretion (mean ± SD) from furosemide alone was 239 ± 90 versus 240 ± 115 mEq/8 h with sulfisoxazole. Sulfisoxazole had modest effects on serum pharmacokinetics of furosemide but had no effect on either the time course of furosemide urinary excretion or overall amount excreted: 49 ± 15 mg versus 54 ± 12 mg for furosemide alone and furosemide plus sulfisoxazole, respectively. It is concluded that urinary protein binding of loop diuretics is not a major mechanism for the diuretic resistance of NS. In turn, strategies aimed at displacing such binding are unlikely to be clinically helpful.
Effect of High Dose Folic Acid Therapy on Hyperhomocysteinemia in Hemodialysis Patients
Authors: SUNDER-PLASSMANN GERE , FO[Combining Diaeresis]DINGER MANUELA , BUCHMAYER HEIDI , PAPAGIANNOPOULOS MENELAOS , WOJCIK JADWIGA , KLETZMAYR JOSEF , ENZENBERGER BRIGITTE , JANATA OSKAR , WINKELMAYER WOLFGANG C. , PAUL GERNOT , AUINGER MARTIN , BARNAS URSULA , HO[Combining Diaeresis]RL WALTER H. 
Published: April 2021

Abstract.
Homocysteine is associated with atherosclerosis and enhanced cardiovascular risk. In previous studies, treatment with folic acid up to 15 mg/d failed to correct hyperhomocysteinemia in the majority of end-stage renal disease patients. A dose of 30 or 60 mg of folic acid per day was compared with 15 mg/d in an attempt to normalize hyperhomocysteinemia in 150 hemodialysis patients. In a randomized, double-blind, multicenter study, 144 patients completed the 4-wk treatment period and 121 patients completed the 6-mo follow-up. Total homocysteine plasma levels were reduced by 32.1% (15 mg/d), 29.9% (30 mg/d), or 37.8% (60 mg/d) with no significant differences found between the three treatment groups. Baseline total homocysteine plasma concentration was an independent predictor of the response to folic acid therapy (P = 0.0001), whereas the 5,10-methylenetetrahydrofolate reductase polymorphisms (MTHFR 677C → T and 1298A → C) had no influence. Nevertheless, patients with the MTHFR 677TT genotype more frequently attained normal total homocysteine plasma levels than patients with the CC or CT genotype (P = 0.025). In response to 60 mg of folic acid per day, TT genotype patients had lower folate plasma levels compared to CC or CT genotype patients (P = 0.016). After completion of the 4-wk treatment period with 30 or 60 mg of folic acid per day, there was a marked rebound of total homocysteine plasma levels at the end of the follow-up in patients with the MTHFR 677TT genotype, which even exceeded baseline values in several patients (P = 0.0001). This study clearly demonstrates that doses of 30 or 60 mg of folic acid per day are not more effective than 15 mg/d in reducing hyperhomocysteinemia in regular hemodialysis patients. Patients with the MTHFR 677TT genotype are more likely to realize normal total homocysteine plasma levels. Folic acid at 30 or 60 mg/d but not 15 mg/d results in a rebound of total homocysteine plasma concentrations when treatment is stopped.
Primary Structure of Mouse and Rat Nephrin cDNA and Structure and Expression of the Mouse Gene
Authors: PUTAALA HELI , SAINIO KIRSI , SARIOLA HANNU , TRYGGVASON KARL 
Published: April 2021

Abstract.
Nephrin is a central component of the glomerular podocyte slit diaphragm and is essential for the normal renal filtration process. This study describes the complete structure of the mouse nephrin gene, which was shown to be homologous to the human gene, the major difference being 30 exons in the mouse gene as opposed to 29 in human. The complete primary structure of mouse and rat nephrins was also determined. The sequence identity between the mouse and rat proteins was shown to be 93%, while both rodent proteins have only about 83% sequence identity with human nephrin. The availability of the three mammalian sequences is significant for the interpretation of sequence variants and mutations in the nephrin gene in patients with congenital nephrotic syndrome. In situ hybridization analyses of whole mouse embryos and tissues revealed high expression of nephrin in kidney glomeruli and, surprisingly, an intense and highly restricted expression in a set of cells in hindbrain and spinal cord. No expression was observed elsewhere. This expression pattern may explain occasionally occurring neural symptoms caused by inactivating mutations in the nephrin gene in patients with congenital nephrotic syndrome.
cAMP Regulates Cell Proliferation and Cyst Formation in Autosomal Polycystic Kidney Disease Cells
Authors: HANAOKA KAZUSHIGE , GUGGINO WILLIAM B. 
Published: April 2021

Abstract.
Both epithelial cell proliferation and fluid accumulation are responsible for cyst growth in autosomal dominant polycystic kidney disease (ADPKD). It was previously reported that the cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in cysts from ADPKD patients and suggested that cAMP-stimulated Cl- and fluid secretion occurs through CFTR. The purpose of this study was to investigate the role of cell proliferation in cyst formation in ADPKD and to explore further the role of fluid secretion in cyst growth. Primary cultures both of ADPKD epithelial cells and a mixed population of normal renal epithelial cells isolated from the cortex (HRCE cells) were used. This study tested whether cAMP was involved both in stimulating cell proliferation and formation of cysts in vitro. 3H-Thymidine incorporation assays showed that epidermal growth factor stimulated proliferation both in ADPKD cells and HRCE cells. In addition, cAMP stimulated DNA synthesis and cell proliferation in ADPKD, but not HRCE, cells. The effects of cAMP and epidermal growth factor on cell growth in ADPKD cells were additive. cAMP also stimulated cyst enlargement and fluid secretion in ADPKD cells. By contrast, cyst formation and enlargement from HRCE cells occurred without cAMP. Fluid secretion into the cyst lumen was blocked by diphenylamine carboxylic acid (DPC) and glibenclamide in ADPKD cells but blocked only by DPC in HRCE cells. This study showed that ADPKD cells have unique characteristics; cAMP stimulates fluid secretion and cell proliferation, indicating cAMP plays a very important role in cyst growth during the course of ADPKD.
Proapoptotic Fas Ligand Is Expressed by Normal Kidney Tubular Epithelium and Injured Glomeruli
Authors: LORZ CORINA , ORTIZ ALBERTO , JUSTO PILAR , GONZÁLEZ-CUADRADO SILVIA , DUQUE NATALIA , GÓMEZ-GUERRERO CARMEN , EGIDO JESÚS 
Published: April 2021

Abstract.
Fas ligand (FasL) is a cell membrane cytokine that can promote apoptosis through activation of Fas receptors. Fas receptor activation induces glomerular cell apoptosis in vivo and participates in tubular cell death during acute renal failure. However, there is little information on the expression of FasL in the kidney. This study reports that FasL mRNA and protein are present in normal mouse and rat kidney. In situ hybridization and immunohistochemistry showed that proximal tubular epithelium is the main site of FasL expression in the normal kidney. In addition, increased total kidney FasL mRNA and de novo FasL protein expression by glomerular cells were observed in two different models of glomerular injury: rat immune-complex proliferative glumerulonephritis and murine lupus nephritis. Both full-length and soluble FasL were increased in the kidneys of the mice with nephritis. Cultured murine proximal tubular epithelial MCT cells and primary cultures of murine tubular epithelial cells expressed FasL mRNA and protein. Tubular epithelium-derived FasL induced apoptosis in Fassensitive lymphoid cell lines but not in Fas-resistant lymphoid cell lines. By contrast, MCT cells grown in the presence of the survival factors of serum were resistant to FasL, and only became partially sensitive to apoptosis induced by high concentrations (100 ng/ml) of FasL upon serum deprivation. However, MCT cells stimulated with inflammatory mediators (tumor necrosis factor-α, interferon-γ, and lipopolysaccharide) increased cell surface Fas expression and were sensitized to apoptosis induced by FasL (FasL 55 ± 5% versus control 8.3 ± 4.1% apoptotic cells at 24 h, P < 0.05). Cytokine-primed primary cultures of tubular epithelial cells also acquired sensitivity to FasL-induced apoptosis. These results suggest that FasL expression by intrinsic renal cells may play a role in cell homeostasis in the normal kidney and during renal injury.
Increases in Serum Leptin Levels during Peritoneal Dialysis Are Associated with Inflammation and a Decrease in Lean Body Mass
Authors: STENVINKEL PETER , LINDHOLM BENGT , LO[Combining Diaeresis]NNQVIST FREDRIK , KATZARSKI KRASSIMIR , HEIMBU[Combining Diaeresis]RGER OLOF 
Published: April 2021

Abstract.
Leptin, secreted from fat cells, functions as a lipostat mechanism through modulation of satiety signals. Markedly elevated leptin levels have been documented in uremic patients, especially in those who are treated by peritoneal dialysis (PD). However, the role of hyperleptinemia in uremic patients is not clear, and it is not known whether elevated leptin levels contribute to uremic anorexia and changes in body composition. In this prospective study, serum leptin, C-reactive protein (CRP), plasma insulin, and body composition (dual-energy x-ray absorptiometry) were measured in 36 patients (53 ± 1 yr) close to start and after about 1 yr of PD. In addition, markers of dialysis adequacy and urea kinetics were followed during treatment with PD. During PD, the total body fat mass (20.5 ± 1.0 to 22.9 ± 1.3 kg; P < 0.01), truncal fat mass (11.5 ± 0.7 to 13.2 ± 0.9 kg; P < 0.001), and serum leptin levels (20.1 ± 3.8 to 35.6 ± 6.8 ng/ml; P < 0.01) increased markedly, especially in patients with diabetes mellitus. Twenty-five PD patients that lost lean body mass during PD had significantly (P < 0.05) elevated initial CRP levels (14 ± 2 mg/L) compared to 11 patients (<10 mg/L) who gained lean body mass during PD. A significant increase in serum leptin levels (20.9 ± 4.2 to 42.7 ± 4.0 ng/ml; P < 0.001) was observed in those patients who lost lean body mass, whereas no such change (18.4 ± 8.4 to 19.2 ± 6.4 ng/ml) was observed in the patients that gained lean body mass during PD treatment. The present longitudinal results demonstrate that serum leptin level and body fat content increase markedly during PD, especially in diabetic patients. Patients that lost lean body mass during PD had higher initial CRP levels and increased their serum leptin levels significantly during PD compared to those patients that gained lean body mass. Additional studies are therefore needed to elucidate the role of hyperleptinemia and inflammation in causing anorexia, protein-malnutrition, and changes in body composition during treatment with PD.
Endothelium-Dependent Relaxation of Small Resistance Vessels Is Impaired in Patients with Autosomal Dominant Polycystic Kidney Disease
Authors: WANG DAN , IVERSEN JENS , STRANDGAARD SVEND 
Published: April 2021

Abstract.
Impaired endothelium-dependent relaxation has been demonstrated previously in resistance vessels of Han:SPRD polycystic kidney disease rats. The aim of the present study was to investigate whether endothelium-dependent relaxation is reduced also in patients with autosomal dominant polycystic kidney disease (ADPKD) and whether this is influenced by the nitric oxide (NO) system. Small subcutaneous resistance vessels from normotensive ADPKD patients with normal or near-normal renal function (n = 9) and from healthy control subjects (n = 10) were mounted in a Mulvany-Halpern myograph. The morphology of the vessels and acetylcholine (ACh)-induced endothelium-dependent relaxation, as well as 3-morpholino-sydnonimine (SIN-1, NO donor)-induced endothelium-independent relaxation were investigated. The results showed that: (1) there were no significant differences in morphologic parameters of resistance vessels between the two groups; (2) the maximal ACh-induced relaxation rate was decreased in ADPKD patients compared with control subjects (71.5 ± 12.1 versus 85.2 ± 8.7%, P < 0.01); (3) in the presence of L-arginine (a substrate of NO synthase), a left shift of the ACh dose-response curves was found in control subjects, but not in ADPKD patients; (4) in the presence of the N
G-nitro-L-arginine methyl ester (an inhibitor of NO synthase), a right shift of the ACh dose-response curve was found in control subjects, but not in ADPKD patients; and (5) endothelium-independent relaxation rate induced with SIN-1 was similar in patients and control subjects. In conclusion, endothelium-dependent relaxation was impaired in resistance vessels from patients with ADPKD. The reduced response of the vessels to both the substrate and inhibitor of NO synthase in ADPKD suggests that an impairment of NO synthase may be involved in the mechanism of endothelial dysfunction in ADPKD.
Metabolism Alters the Selectivity of Angiotensin-(1-7) Receptor Ligands for Angiotensin Receptors
Authors: HANDA RAJASH K. 
Published: April 2021

Abstract.
The present study examined whether metabolism of the putative angiotensin-(1-7) receptor agonist and antagonist [angiotensin-(1-7) and D-alanine7 angiotensin-(1-7), respectively] altered their ability to interact with angiotensin AT1, AT2, and AT4 receptor subtypes. Both angiotensin-(1-7) and D-alanine7 angiotensin-(1-7) competed with low affinity for 125I-sarcosine1, isoleucine8 angiotensin II binding to AT1 and AT2 receptors in rat liver and adrenal medulla membranes, respectively, and competed with low affinity for 125I-angiotensin IV binding to AT4 receptors in bovine kidney epithelial cell membranes. In vitro renal metabolism of the angiotensin-(1-7) receptor ligands (incubating peptides with rat cortical tissue homogenates) had minimal influence on low-affinity binding to AT1 and AT2 receptors, yet caused a significant and dramatic shift toward high-affinity binding for AT4 receptors. Low-affinity angiotensin II binding to the AT4 receptor was also shifted toward high-affinity binding following renal metabolism of the peptide. Conversely, angiotensins with high affinity for the AT4 receptor (e.g., angiotensin IV) were shifted toward low-affinity binding states following peptide metabolism. Incubation of 125I-angiotensin-(1-7) with rat cortical tissue generated the high-affinity AT4 receptor ligand 125I-angiotensin-(3-7), whereas the renal metabolism of 125I-angiotensin II generated both 125I-angiotensin-(3-7) and 125I-angiotensin IV. These results reveal that renal metabolism of angiotensin-(1-7) receptor ligands and angiotensin II yields products that have high affinity for the AT4 receptor and could potentially contribute to the biologic actions of the parent peptide in the kidney.
Gastrin Releasing Peptide-Preferring Bombesin Receptors Mediate Growth of Human Renal Cell Carcinoma
Authors: PANSKY ANDREAS , DE WEERTH ANDREAS , FASLER-KAN ELIZAVETA , BOULAY JEAN-LOUIS , SCHULZ MARTINA , KETTERER SYLVIA , SELCK CRISTIN , BEGLINGER CHRISTOPH , VON SCHRENCK TAMMO , HILDEBRAND PIUS 
Published: April 2021

Abstract.
Bombesin-like peptides typically act as neurotransmitters along the brain-gut axis and as growth factors in various human tissues. The present study demonstrates the expression of gastrin releasing peptide (GRP)-preferring bombesin receptors in human renal cell carcinoma but not in normal kidney tissue. The expression of GRP receptors was characterized at the mRNA level by reverse transcription-PCR, as well as at the protein level by binding of 125I-[Tyr4] bombesin to membranes prepared from tumor tissue (K
d 0.3 nM) and healthy kidney tissue from the same four patients. GRP receptors were also demonstrated in four human kidney carcinoma cell lines (A-498, CAKI-1, CAKI-2, and ACHN). The effects of bombesin/GRP agonists and/or antagonists on growth were investigated in vitro on CAKI-2 cells, which expressed large amounts of GRP receptors. Cell numbers stimulated by 10% fetal calf serum were significantly stimulated by interleukin-1β (control) and GRP-7 (10-7 M), both in the range of 136 to 148%; addition of the GRP receptor antagonist acetyl-GRP(20-27) (10-6 M) completely reversed this effect. Bombesin alone (10-6 M) significantly stimulated CAKI-2 cells (129%) cultured with 0.5% fetal calf serum, whereas another antagonist, D-Phe6,Leu13,(CH2NH)Leu14 bombesin(6-14) (1 μM), alone did not inhibit growth, thus excluding an autocrine mechanism. These results indicate for the first time that malignant transformation of human kidney tissue into renal cell carcinoma is accompanied by novel expression of GRP receptors. Bombesin-like peptides might act as mitogens in these carcinomas, and they might be useful as diagnostic or therapeutic tools such as tumor imaging or internal radiotherapy.
Mutations in the Chloride Channel Gene CLCNKB as a Cause of Classic Bartter Syndrome
Authors: KONRAD MARTIN , VOLLMER MARTIN , LEMMINK HENNY H. , VAN DEN HEUVEL LAMBERTUS P. W. J. , JECK NIKOLA , VARGAS-POUSSOU ROSA , LAKINGS ALICIA , RUF RAINER , DESCHE[Combining Circumflex Accent]NES GEORGES , ANTIGNAC CORINNE , GUAY-WOODFORD LISA , KNOERS NINE V. A. M. , SEYBERTH HANNSJO[Combining Diaeresis]RG W. , FELDMANN DELPHINE , HILDEBRANDT FRIEDHELM 
Published: April 2021

Abstract.
Inherited hypokalemic renal tubulopathies are differentiated into at least three clinical subtypes: (1) the Gitelman variant of Bartter syndrome (GS); (2) hyperprostaglandin E syndrome, the antenatal variant of Bartter syndrome (HPS/aBS); and (3) the classic Bartter syndrome (cBS). Hypokalemic metabolic alkalosis and renal salt wasting are the common characteristics of all three subtypes. Hypocalciuria and hypomagnesemia are specific clinical features of Gitelman syndrome, while HPS/aBS is a life-threatening disorder of the newborn with polyhydramnios, premature delivery, hyposthenuria, and nephrocalcinosis. The Gitelman variant is uniformly caused by mutations in the gene for the thiazide-sensitive NaCl-cotransporter NCCT (SLC12A3) of the distal tubule, while HPS/aBS is caused by mutations in the gene for either the furosemide-sensitive NaK-2Cl-cotransporter NKCC2 (SLC12A1) or the inwardly rectifying potassium channel ROMK (KCNJ1). Recently, mutations in a basolateral chloride channel CLC-Kb (CLCNKB) have been described in a subset of patients with a Bartter-like phenotype typically lacking nephrocalcinosis. In this study, the screening for CLCNKB mutations showed 20 different mutations in the affected children from 30 families. The clinical characterization revealed a highly variable phenotype ranging from episodes of severe volume depletion and hypokalemia during the neonatal period to almost asymptomatic patients diagnosed during adolescence. This study adds 16 novel mutations to the nine already described, providing further evidence that mutations in the gene for the basolateral chloride channel CLC-Kb are the molecular basis of classic Bartter syndrome. Interestingly, the phenotype elicited by CLCNKB mutations occasionally includes HPS/aBS, as well as a Gitelman-like phenotype.
Retinoic Acid Reduces Glomerular Injury in a Rat Model of Glomerular Damage
Authors: WAGNER JU[Combining Diaeresis]RGEN , DECHOW CLAUDIUS , MORATH CHRISTIAN , LEHRKE INGO , AMANN KERSTIN , WALDHERR RU[Combining Diaeresis]DIGER , FLOEGE JU[Combining Diaeresis]RGEN , RITZ EBERHARD 
Published: April 2021

Abstract.
In the reaction of kidneys to injury, cytokine-driven proliferation plays an important role and precedes the development of glomerulosclerosis. There is great interest in agents that may interfere with such proliferation. Therefore, a rat model of mesangioproliferative glomerulonephritis (induced by anti-Thy1.1) was studied, and the effects of all-trans-retinoic acid (all-trans-RA) and isotretinoin, powerful antiproliferative and anti-inflammatory substances, on glomerular damage and cell proliferation were examined. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of 10 mg/kg body wt all-trans-RA or 40 mg/kg body wt isotretinoin (n = 9 to 11 per group), using either a pretreatment (days -2 through 8) or posttreatment (days +3 through +8) protocol, i.e., starting before or after the induction of anti-Thy1.1 nephritis, respectively. All-trans-RA prevented the BP increase evoked by anti-Thy1.1 (anti-Thy1.1/vehicle, 112.2 ± 4.8 mmHg; anti-Thy1.1/RA, 87.5 ± 2.5 mmHg; P < 0.001). Treatment with all-trans-RA or isotretinoin produced a 70% decrease in the urinary albumin excretion rate (P < 0.02). Periodic acid-Schiff staining of saline-perfused kidneys (day 8) revealed significantly fewer glomerular cells in RA-treated nephritic rats (anti-Thy1.1/vehicle, 97 ± 3.1 cells/glomerulus; anti-Thy1.1/RA, 80 ± 4.4; P < 0.02; control/vehicle, 69 ± 1.2). No difference was observed between all-trans-RA and isotretinoin treatment. The capillary occlusion scores were significantly lower for the anti-Thy1.1/RA-treated group (1.9 ± 0.1) than for the anti-Thy1.1/vehicle-treated group (2.9 ± 0.5, P < 0.001). In the anti-Thy1.1/vehicle-treated group, 11.9 ± 1.1 glomerular cells were proliferating cell nuclear antigen-positive; however, in the anti-Thy1.1/RA-treated group, only 5.3 ± 0.8 cells were proliferating cell nuclear antigen-positive (P < 0.002; control, 2.2 ± 0.2). Glomerular mitoses were reduced by 67% in the anti-Thy1.1/RA-treated group, compared with the anti-Thy1.1/control group (P < 0.002). Glomerular staining for platelet-derived growth factor B-chain was significantly reduced in anti-Thy1.1-treated nephritic rats in the presence of isotretinoin or all-trans-RA, compared with the vehicle-treated group (P < 0.001). It is concluded that all-trans-RA limits glomerular proliferation, glomerular lesions, and albuminuria in an established model of renal damage. The findings point to retinoids as potential novel modulators of glomerular injury.