bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Locus for Adolescent and Adult Onset Familial Focal Segmental Glomerulosclerosis on Chromosome 1q25-31
Authors: TSUKAGUCHI HIROYASU , YAGER HENRY , DAWBORN JOHN , JOST LUIS , COHLMIA JERRY , ABREU PATRICIA F. , PEREIRA APARECIDO B. , POLLAK MARTIN R. 
Published: April 2021

Abstract.
Focal segmental glomerulosclerosis is a nonspecific renal lesion observed both as a primary (idiopathic) entity and in a secondary form, typically in association with reduced functional renal mass. Familial forms have been observed and two loci for autosomal dominant FSGS have been mapped. This study shows that an adolescent/adult form of recessive FSGS maps to a locus on chromosome 1q25-31, which overlaps with a region previously identified as harboring a locus for an early childhood onset recessive form of nephrotic syndrome (SRN1). Evaluation of a large family demonstrated linkage with a maximum two-point lod score of 3.98 at D1S254 and D1S222. Lod score calculations support the conclusion of linkage in four of five additional families. Haplotype analysis suggests that this FSGS gene is located in a 19-cM region flanked by D1S416 and D1S413, of which 6 cM overlaps with SRN1, suggesting that these distinct clinical subsets of kidney disease may be allelic. These regions may also overlap with the syntenic region of the glomerulosclerosis susceptibility locus in the BUF/Mna rat. Because the presentation of FSGS may be subtle, inherited FSGS may be much more common than generally realized and grossly underestimated because of the absence of clear familial patterns. This result increases the suspicion that polymorphisms at this locus may contribute to sporadic FSGS.
Induction of CD14 in Tubular Epithelial Cells During Kidney Disease
Authors: MORRISSEY JEREMIAH , GUO GUANGJIE , MCCRACKEN RUTH , TOLLEY TIMOTHY , KLAHR SAULO 
Published: April 2021

Abstract.
Analysis of gene expression in a mouse model of unilateral ureteral obstruction (UUO) revealed significant induction of CD14 mRNA in kidneys with obstructed ureters. Immunocytochemical analysis indicated that CD14 was upregulated in tubular epithelial cells and this upregulation was not attributable to infiltration of the kidneys by mononuclear cells. This induction of CD14 mRNA was found to occur in BALB/C, C57BL/6, C3H/HeN, and C3H/HeJ mice during UUO. Ischemia/reperfusion of kidneys also induced CD14 mRNA. Mice lacking either of the tumor necrosis factor-α receptor (TNFR) genes were also studied; the induction of CD14 was blunted in TNFR 1-knockout mice but not in TNFR2-knockout mice. Apoptosis of tubular cells in lipopolysaccharide-resistant CH3/HeJ mice was significantly (P < 0.05) less than that in lipopolysaccharide-responsive CH3/HeN mice during UUO. These results suggest that CD14 is acutely induced in tubular epithelial cells in two mouse models of renal injury. This induction is regulated by tumor necrosis factor-α, through TNFR1. CD14 may participate in the apoptosis of tubular epithelial cells on a more chronic basis by activating a pathway that is absent or deficient in C3H/HeJ mice.
Mechanism of the Inhibitory Effect of OPB-9195 [(±)-2-Isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide] on Advanced Glycation End Product and Advanced Lipoxidation End Product Formation
Authors: MIYATA TOSHIO , UEDA YASUHIKO , ASAHI KOICHI , IZUHARA YUKO , INAGI REIKO , SAITO AKIRA , VAN YPERSELE DE STRIHOU CHARLES , KUROKAWA KIYOSHI 
Published: April 2021

Abstract.
The accumulation in uremic plasma of reactive carbonyl compounds (RCO) derived from both carbohydrates and lipids (“carbonyl stress”) contributes to uremic toxicity by accelerating the advanced glycation and lipoxidation of proteins. It was previously demonstrated that OPB-9195 [(±)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide] inhibited the in vitro formation of advanced glycation end products (AGE) in uremic plasma. This study was designed to elucidate the mechanism of action of OPB-9195 by further delineating the AGE and advanced lipoxidation end product (ALE) precursors targeted by this drug. The inhibitory effects of OPB-9195 on the formation of two AGE (Nε-carboxymethyllysine and pentosidine) on bovine serum albumin incubated with various AGE precursors were examined. Inhibition of Nε-carboxymethyllysine and pentosidine formation with OPB-9195 was more efficient than with aminoguanidine. OPB-9195 also proved effective in blocking the carbonyl amine chemical processes involved in the formation of two ALE (malondial-dehyde-lysine and 4-hydroxynonenal-protein adduct). The efficiency of OPB-9195 was similar to that of aminoguanidine. When glucose-based peritoneal dialysis fluid was incubated in the presence of OPB-9195, a similar inhibition of AGE formation was observed. The direct effect of OPB-9195 on major glucose-derived RCO in peritoneal dialysis fluids was then evaluated. The effects of OPB-9195 could be accounted for by its ability to trap RCO. The concentrations of three major glucose-derived RCO (glyoxal, methylglyoxal, and 3-deoxy-glucosone) were significantly lower in the presence of OPB-9195 than in its absence. Aminoguanidine had a similar effect. In conclusion, OPB-9195 inhibits both AGE and ALE formation, probably through its ability to trap RCO. OPB-9195 might prove to be a useful tool to inhibit some of the effects of RCO-related uremic toxicity.
Increased Albumin and Fibrinogen Synthesis in Hemodialysis Patients with Normal Nutritional Status
Authors: GIORDANO MAURO , FEO PIERPAOLO DE , LUCIDI PAOLA , dePASCALE EMANUELA , GIORDANO GELSOMINA , INFANTONE LORENA , ZOCCOLO ANNA MARIA , CASTELLINO PIETRO 
Published: April 2021

Abstract.
This study compared the rates of whole-body proteolysis and of albumin and fibrinogen synthesis of seven hemodialysis patients (HD) with those of seven normal matched control subjects (C). HD patients had a normal nutritional and inflammatory status and serum albumin levels >3.5 g/dl. Endogenous leucine flux, albumin and fibrinogen fractional synthesis rate (FSR), and absolute intravascular synthesis rate (ASR) of albumin and fibrinogen all were evaluated by a primed/continuous infusion of 5,5,5-D3-L-leucine. Plasma volume was determined by the Evans blue dye dilution method. Endogenous leucine flux was significantly increased in HD (2.64 ± 0.08 μmol/kg per min) compared with C (2.17 ± 0.07 μmol/kg per min, P < 0.05). Serum albumin concentrations were similar in HD and C. Plasma fibrinogen levels were significantly increased in HD compared with C (P < 0.05). Plasma volume was greater in HD than in C (P < 0.05). As a result, total intravascular pool of both albumin (141 ± 7 versus 114 ± 3 g/1.73 m2, P < 0.05) and fibrinogen (11.7 ± 1 versus 6.7 ± 0.5 g/1.73 m2, P < 0.05) were greater in HD than in C. Albumin FSR was not statistically different in HD and C. However, albumin ASR was significantly increased in HD than in C (13.7 ± 2 versus 10.3 ± 1 g/1.73 m2 per d, P < 0.05). Similarly, FSR of fibrinogen did not differ in HD and C groups, whereas ASR of fibrinogen was significantly higher in HD than in C (3.31 ± 0.6 versus 1.94 ± 0.3 g/1.73 m2 per d, P < 0.05). In summary, normoalbuminemic HD patients have an increased intravascular pool with a greater absolute synthesis rate of both albumin and fibrinogen and an increased rate of whole-body leucine flux.
Limitations in Anthropometric Calculations of Total Body Water in Patients on Peritoneal Dialysis
Authors: JOHANSSON ANN CATHRINE , SAMUELSSON OLA , ATTMAN PER OLA , BOSAEUS INGVAR , HARALDSSON BO[Combining Diaeresis]RJE 
Published: April 2021

Abstract.
Having an accurate estimation of total body water (TBW) is essential for the evaluation of dialysis efficacy in peritoneal dialysis (PD) patients. In this study, TBW volumes were measured by tritium dilution (TBWTHO) in 165 PD patients and compared with TBW calculations according to the Watson formulas. An alternative anthropometric formula based on the present PD population was also developed and validated in an independent sample of 29 PD patients. Furthermore, the relation between TBWTHO and body surface area (BSA) according to the formula of Gehan was analyzed. Body composition was assessed by a four-compartment model, based on measurements of TBWTHO and total body potassium. Mean values of TBW by the Watson formulas were almost identical to TBWTHO, and the correlation coefficient for the relationship of calculated to measured volumes was 0.89 (P = 0.001). However, both anthropometric formulas—the Watson formulas as well as the new, alternative one—overestimated TBW in obese patients and vice versa in lean patients. Similarly, TBW was underestimated in patients who were overhydrated. The correlation coefficient between TBWTHO and BSA was 0.708 for males and 0.797 for females (P = 0.0001 for both). In obese patients, the relationship was even closer (r = 0.924 and 0.911, respectively). In conclusion, anthropometric formulas to calculate TBW showed a considerable intraindividual variability compared with measured values. This was related to body composition features, such as degree of obesity and hydration. In contrast, BSA correlated closely to TBW in obese individuals. TBW as estimated by anthropometric formulas must be analyzed with caution, especially in the very obese or very lean patient.
Lowering of Microalbuminuria in Diabetic Patients by a Sympathicoplegic Agent
Authors: STROJEK KRZYSZTOF , GRZESZCZAK WLADYSLAW , GÓRSKA JUTA , LESCHINGER MONIKA I. , RITZ EBERHARD 
Published: April 2021

Abstract.
There is convincing evidence for a specific BP-independent effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on albuminuria in glomerular disease. Because progression of glomerular disease is not consistently halted by these agents, there is a need to explore potential renoprotective effects of other drugs. Recent animal work documented that nonhypotensive doses of moxonidine, a sympathicoplegic agent, reduce albuminuria and development of glomerulosclerosis in a BP-independent manner. A randomized, crossover design was used to assess the human relevance of the experimental data in 15 normotensive, nonsmoking type 1 diabetic mellitus patients with good glycemic control (age, 37.3 ± 6.6 yr; 9 men/6 women; duration of diabetes, 23.6 ± 5.1 yr) with baseline urinary albumin excretion rates (AER) >20 μg/min in the run-in phase. AER was assessed in overnight timed urine collections. The patients were assigned to a 3-wk placebo and a 3-wk moxonidine (0.2 mg twice a day) period, respectively, in random order. This dose causes modest BP lowering in hypertensive individuals but does not affect BP in normotensive individuals. There was no significant effect on ambulatory BP (mean arterial pressure, 91.8 ± 7.1 mmHg in the third week of placebo and 91.1 ± 8.7 mmHg on moxonidine). There was a significant (P < 0.006) difference of the treatment effects between placebo and moxonidine, respectively, on AER; median AER at the end of the placebo period was 39.8 μg/min (range, 15.9 to 117 μg/min) versus 29.0 (range, 9.03 to 85.8 μg/min) at the end of the moxonidine period. The data document an antialbuminuric effect of nonhypotensive doses of moxonidine. Diminished sympathetic traffic to the kidney is the most plausible explanation for the finding.
Induction of Cyclooxygenase-2 in Thick Ascending Limb Cells by Adrenalectomy
Authors: VIO CARLOS P. , AN SHAO-JIAN , CÉSPEDES CARLOS , MCGIFF JOHN C. , FERRERI NICHOLAS R. 
Published: April 2021

Abstract.
Adrenalectomized (ADX) and sham-operated rats received either dexamethasone (DEX) or vehicle. Renal tissue was used for morphologic analysis, assessment of cyclooxygenase-2 (COX-2) protein expression and mRNA accumulation, and quantitation of COX-2 activity. In untreated or shamoperated rats, COX-2 protein was observed in a subset of tubular epithelial cells (<2%), which were located mainly in the cortex. All COX-2-positive cells also expressed Tamm-Horsfall glycoprotein, a highly selective marker for thick ascending limb (TAL) cells. After ADX, >30% of TAL cells expressed COX-2 in a manner consistent with recruitment of COX-2-positive TAL cells toward the medulla. Treatment of ADX rats with DEX reduced the number of COX-2-positive cells to that observed in sham-operated or intact rats. COX-2 mRNA accumulation was increased by ADX and partially attenuated by treatment with DEX. Western blot analysis of cortical microsomes revealed a substantial increase in COX-2 expression in ADX rats, compared with ADX/DEX-treated, sham-operated, or intact rats. The increase in COX-2 protein expression was associated with a twofold increase in prostaglandin E2 formation by cortical microsomes obtained from ADX rats, compared with sham-operated rats. It is concluded that ADX induces expression of enzymatically active COX-2, such that expression occurs in the cortical TAL and proceeds in a defined pattern toward the outer medullary TAL. It is suggested that ADX induces expression of TAL cells that, in the basal state, do not express COX-2 protein.
The Membrane-Associated Guanylate Kinase Protein MAGI-1 Binds Megalin and Is Present in Glomerular Podocytes
Authors: PATRIE KEVIN M. , DRESCHER ANDREW J. , GOYAL MEERA , WIGGINS ROGER C. , MARGOLIS BEN 
Published: April 2021

Abstract.
The transmembrane endocytic receptor glycoprotein 330/megalin (hereafter referred to as megalin) is localized to the apical membrane domain of epithelial cells, where it is involved in the uptake of proteins from extracellular sources. The cytoplasmic domain of megalin contains amino acid motifs that have the potential to bind to other proteins, which may influence its localization or function. The yeast two-hybrid system was used to search for proteins that bind to the cytoplasmic tail of megalin, and a protein fragment from a mouse embryonic cDNA library that contained a single PDZ domain was identified. This protein, which was named glycoprotein 330-associated protein (GASP), appears to be a truncated mouse counterpart of the human and rat proteins atrophin-1-interacting protein-1 and synaptic scaffolding molecule, respectively. The interaction of GASP with megalin is mediated by the PDZ domain of GASP binding to the DSDV motif found at the carboxyl-terminus of megalin. A mutant version of megalin that lacks the terminal valine is unable to bind to GASP, illustrating the PDZ domain-dependent interaction between these two proteins. A close homolog of GASP, i.e., membrane-associated guanylate kinase with inverted orientation-1 (MAGI-1), is more ubiquitous in its tissue distribution (including kidney) and is also able to specifically bind to megalin via its fifth PDZ domain. Immunofluorescence studies of adult kidney revealed that MAGI-1 is expressed in the glomerulus of the kidney, in a manner that parallels the expression of the podocyte-specific protein glomerular epithelial protein 1. Western analysis of endogenous MAGI-1 from glomerular preparations suggests that it is associated with the cytoskeleton and seems to be expressed in a different form, compared with cell line-derived endogenous MAGI-1. The association of megalin with MAGI-1 may allow the assembly of a multiprotein complex, in which megalin may serve a nonendocytic function in glomerular podocytes.
Acetylcholine Increases the Free Intracellular Calcium Concentration in Podocytes in Intact Rat Glomeruli via Muscarinic M5 Receptors
Authors: NITSCHKE ROLAND , HENGER ANNA , RICKEN SIGRID , MU[Combining Diaeresis]LLER VICTORIA , KO[Combining Diaeresis]TTGEN MICHAEL , BEK MARTIN , PAVENSTA[Combining Diaeresis]DT HERMANN 
Published: April 2021

Abstract.
The effects of acetylcholine (ACh) on the free intracellular calcium concentration ([Ca2+]i) of microdissected glomeruli were investigated using fura-2 fluorescence digital imaging and two-photon confocal microscopy. ACh caused a concentration-dependent [Ca2+]i increases with an initial peak followed by a sustained plateau, which was suppressed by reduced extracellular Ca2+ concentrations. The [Ca2+]i plateau was not affected by the L-type Ca2+ channel blocker nicardipine, whereas gadolinium and lanthanum (both at 1 μM) blocked the plateau. Diphenylacetoxy-N-methylpiperidine methiodide (100 nM), an M3/M5 receptor antagonist, and pirenzepine (1 μM), an M1 receptor antagonist, completely inhibited the effect of ACh. [Ca2+]i measurements using two-photon excitation of fluo-3 and staining of the cells with calcein/acetoxymethyl ester, for observation of the capillary network together with the glomerular cells, showed that [Ca2+]i was increased in single podocytes. Immunohistochemical studies did not demonstrate M3 receptor expression in glomerular cells. M1 receptors could be detected only in the parietal sheet of Bowman's capsule, whereas M5 receptors were found only in podocytes. The data show that ACh increases [Ca2+]i in podocytes of intact glomeruli, most likely via muscarinic M5 receptors.
Novel Nonsense Mutation in the Na+/HCO3 - Cotransporter Gene (SLC4A4) in a Patient with Permanent Isolated Proximal Renal Tubular Acidosis and Bilateral Glaucoma
Authors: IGARASHI TAKASHI , INATOMI JUN , SEKINE TAKASHI , SEKI GEORGE , SHIMADZU MITSUNOBU , TOZAWA FUMIKO , TAKESHIMA YASUHIRO , TAKUMI TORU , TAKAHASHI TOSHIKAZU , YOSHIKAWA NORISHIGE , NAKAMURA HAJIME , ENDOU HITOSHI 
Published: April 2021

Abstract.
Permanent isolated proximal renal tubular acidosis (pRTA) with ocular abnormalities is a systemic disease involving short stature, isolated pRTA, mental retardation, and ocular abnormalities. Kidney Na+/HCO3
- cotransporter (kNBC1) cDNA from peripheral lymphocytes from a patient with permanent isolated pRTA and bilateral glaucoma was screened, and a novel homozygous mutation, namely a cytosine-to-thymine transition at nucleotide 234, which resulted in the formation of a stop codon at codon 29, was identified. This homozygous mutation, Q29X, was identified in the unique 5′-end of the kNBC1 gene (SLC4A4) of the patient. Cosegregation of this Q29X mutation with the disease and heterozygosity in the parents of the affected patient were observed. The absence of this mutation in 156 alleles from 78 Japanese individuals indicates that this mutation is directly related to the disease and is not a common DNA sequence polymorphism. This nonsense mutation predicts a truncated kNBC1 protein that lacks the 1007 amino acids of the carboxyl-terminus, and the effect on kNBC1 cotransport activity is likely to be a loss of function. In contrast, the pancreatic Na+/HCO3
- cotransporter of the patient is not likely to be affected by this nonsense mutation. These results have implications for understanding the role of kNBC1 in the pathophysiologic processes of pRTA associated with ocular abnormalities and mental retardation.
Mutation Analysis of the Entire Replicated Portion of PKD1 Using Genomic DNA Samples
Authors: PHAKDEEKITCHAROEN BUNYONG , WATNICK TERRY J. , GERMINO GREGORY G. 
Published: April 2021

Abstract.
The replicated portion of PKD1, which comprises nearly 70% of the length of the gene, is predicted to harbor at least 85% of the mutations present in affected autosomal dominant polycystic kidney disease type 1 pedigrees. The relative paucity of reported mutations involving this segment is attributable to the significant technical challenges posed by the genomic structure of the gene. Previous genomic DNA-based strategies were unable to evaluate exons 1 and 22 and relied on the use of 10- to 13-kb PCR products. In this report, a set of six novel primer pair combinations, which can be used with previously reported reagents to analyze all of the exons in the replicated region (exons 1 to 34), are described. No product is greater than 5.8 kb in length, and various primer combinations can be used to reduce this length in half. Using this approach, two new pathogenic mutations, four novel disease-associated missense substitutions, and six new normal variants were identified. These new reagents should prove useful to investigators interested in performing DNA testing for this disorder.
Role of p53-Dependent Activation of Caspases in Chronic Obstructive Uropathy: Evidence from p53 Null Mutant Mice
Authors: CHOI YEONG-JIN , MENDOZA LEONARDO , RHA SUK-JOO , SHEIKH-HAMAD DAVID , BARANOWSKA-DACA ELZBIETA , NGUYEN VINH , SMITH WAYNE C. , NASSAR GEORGE , SUKI WADI N. , TRUONG LUAN D. 
Published: April 2021

Abstract.
Chronic obstructive uropathy (COU) created by unilateral ureteric ligation is associated with increased renal cell apoptosis and p53 expression. Genetically engineered mice were used to examine the role of p53 in renal cell apoptosis in COU and the involved molecular pathways. Obstructed kidneys in p53+/+, p53+/-, and p53-/- mice were examined at days 4, 7, 15, 20, and 30 for apoptosis, and mRNA were examined for p53, members of the bcl-2 family, the death receptor family, and the common effectors of apoptosis. Obstructed kidneys in p53+/- and p53-/- mice exhibited equal attenuation of tubular and interstitial cell apoptosis (70 and 50%, respectively), compared with p53+/+ mice. However, p53 gene deficiency did not confer complete protection from apoptosis. Obstructed kidneys from p53-/- mice did not express p53 mRNA, whereas those from p53+/- and p53+/+ mice displayed mild and marked increase in their expression, respectively. Obstructed kidneys in p53+/+, p53+/-, and p53-/- mice displayed upregulation of mRNA for members of the bcl-2 family and most of the death receptor family, except for a lower level of tumor necrosis factor receptor-1, TRAIL, and FAP in p53+/+ mice. Obstructed kidneys in p53-/- and p53+/- mice showed virtual absence of caspase 11 and marked attenuation of caspases 1 and 12, contrasted with their strong expression in p53+/+ kidneys. These data suggest that apoptosis in obstructed kidneys involves p53-dependent as well as p53-independent pathways. The p53-dependent pathway may involve activation of caspases 1, 11, and 12, whereas the p53-independent pathway may involve activation of members of the bcl-2 and death receptor families.
Glomerular Injury and Tubular Loss in Adriamycin Nephrosis
Authors: JAVAID BASIT , OLSON JEAN L. , MEYER TIMOTHY W. 
Published: April 2021

Abstract.
Glomerular injury manifested by sustained proteinuria usually leads to tubule injury and reduction of the GFR. The current study explored the link between these processes in rats with adriamycin nephrosis. One group of nephrotic rats received a vasopressin V2 receptor blocker (V2X) from 4 to 16 wk after injection of adriamycin, whereas a second group received no treatment (NoRx). V2 receptor blockade increased urine volume without affecting protein excretion. At 16 wk, both groups of nephrotic rats exhibited a marked reduction in GFR in comparison with normal controls (V2X, 0.22 ± 0.19 ml/min; NoRx, 0.20 ± 0.11 ml/min; control, 1.23 ± 0.11 ml/min). Morphologic studies revealed that the majority of glomeruli in nephrotic rats were no longer connected to normal tubule segments (V2X, 81 ± 21%; NoRx, 85 ± 18%; control, 1 ± 2%). Glomeruli without tubules were not, however, globally sclerosed. Disruption of the glomerular tubular junction was associated with the presence of amorphous material separating damaged tubule cells from the basement membrane. Serial sections revealed that this material spread from extensive areas of adhesion between the glomerular tuft and capsule to invest the tubular neck. Reduction of the GFR was strongly correlated with the fraction of glomeruli not connected to normal tubules (r
2 = 0.82; P < 0.0001). V2 receptor blockade did not preserve renal function or structure. These findings suggest that local extension of glomerular injury to destroy the tubule neck is an important cause of loss of renal function in adriamycin nephrosis.