bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomics and the Kidney
Authors: Knepper Mark A. 
Published: October 2004

ABSTRACT.
Proteomics can be defined as “the systematic analysis of proteins for their identity, quantity, and function.” The central concept is “multiplexing,” i.e., simultaneous analysis of all proteins in a defined protein population, rather than investigation of one protein at a time, as in traditional biochemistry. Two major approaches have been described: (1) mass spectrometry-based approaches and (2) protein micro-array approaches. The purpose of this Science Watch article is to describe the fundamental features of these two approaches and to speculate on how proteomics will be useful in nephrology and nephrology research in the coming years.
Purinergic Receptor Signaling at the Basolateral Membrane of Macula Densa Cells
Authors: Liu Ruisheng , Bell P. Darwin , Peti-Peterdi Janos , Kovacs Gergly , Johansson Alf , Persson A. Erik G. 
Published: October 2004

ABSTRACT.
Purinergic receptors are important in the regulation of renal hemodynamics; therefore, this study sought to determine if such receptors influence macula densa cell function. Isolated glomeruli containing macula densa cells, with and without the cortical thick ascending limb, were loaded with the Ca2+ sensitive indicators, Fura Red (confocal microscopy) or fura 2 (conventional video image analysis). Studies were performed on an inverted microscope in a chamber with a flow-through perfusion system. Changes in cytosolic calcium concentration ([Ca2+]i) from exposed macula densa plaques were assessed upon addition of adenosine, ATP, UTP, ADP, or 2-methylthio-ATP (2- MeS-ATP) for 2 min added to the bathing solution. There was no change in [Ca2+]i with addition of adenosine (10−7 to 10−3 M). UTP and ATP (10−4 M) caused [Ca2+]i to increase by 268 ± 40 nM (n = 21) and 295 ± 53 nM (n = 21), respectively, whereas in response to 2MesATP and ADP, [Ca2+]i increased by only 67 ± 13 nM (n = 8) and 93 ± 36 nM (n = 14), respectively. Dose response curve for ATP (10−7 to 10−3 M) added in bath showed an EC50 of 15 μM. No effect on macula densa [Ca2+]i was seen when ATP was added from the lumen. ATP caused similar increases in macula densa [Ca2+]i in the presence or absence of bath Ca2+ and addition of 5 mM ethyleneglycotetraacetic acid (EGTA). Suramin (an antagonist of P2X and P2Y receptors) completely inhibited ATP-induced [Ca2+]i dynamics. Also, ATP-Ca2+ responsiveness was prevented by the phospholipase C inhibitor, U-73122, but not by its inactive analog, U-73343. These results suggest that macula densa cells possess P2Y2 purinergic receptors on basolateral but not apical membranes and that activation of these receptors results in the mobilization of Ca2+.
Hepatitis C and Renal Transplantation in the Era of Modern Immunosuppression
Authors: Abbott Kevin C. , Bucci Jay R. , Matsumoto Cal S. , Swanson S. John , Agodoa Lawrence Y.C. , Holtzmuller Kent C. , Cruess David F. , Peters Thomas G. 
Published: October 2004

ABSTRACT.
Kidneys from donors who are positive for hepatitis C virus (DHCV+) have recently been identified as an independent risk factor for mortality after renal transplantation. However, it has not been determined whether risk persists after adjustment for baseline cardiac comorbidity or applies in the era of modern immunosuppression. Therefore, a historical cohort study was conducted of US adult cadaveric renal transplant recipients from January 1, 1996, to May 31, 2001; followed until October 31, 2001. A total of 36,956 patients had valid donor and recipient HCV serology. Cox regression analysis was used to model adjusted hazard ratios for mortality and graft loss, respectively, adjusted for other factors, including comorbid conditions from Center for Medicare and Medicaid Studies Form 2728 and previous dialysis access-related complications. It was found that DHCV+ was independently associated with an increased risk of mortality (adjusted hazard ratio, 2.12, 95% confidence interval, 1.72 to 2.87; P < 0.001), primarily as a result of infection. Mycophenolate mofetil was associated with improved survival in DHCV+ patients, primarily related to fewer infectious deaths. Adjusted analyses limited to recipients who were HCV+, HCV negative, or age 65 and over, or by use of mycophenolate mofetil confirmed that DHCV+ was independently associated with mortality in each subgroup. It is concluded that DHCV+ is independently associated with an increased risk of mortality after renal transplantation adjusted for baseline comorbid conditions in all subgroups. Recipients of DHCV+ organs should be considered at high risk for excessive immunosuppression. E-mail: kevin.abbott@ na.amedd.army.mil
Urea Restrains Aldosterone-Induced Development of Peanut Agglutinin–Binding on Embryonic Renal Collecting Duct Epithelia
Authors: Schumacher Karl , Strehl Raimund , Minuth Will W. 
Published: October 2004

ABSTRACT.
Peanut agglutinin (PNA) represents a commonly used marker for β-type intercalated (IC) cells and their distribution in the corticomedullary course of the collecting duct (CD) in the mature rabbit kidney. It has been shown that aldosterone is able to generate >90% of PNA-binding cells in an embryonic CD epithelium in vitro. In adult kidney, a maximum of only 25% PNA-positive cells is found in the cortical segment of the CD, and PNA-binding completely disappears in the inner-medullary CD. Molecules that regulate the gradual development of CD-specific cells during organ growth are unknown. In the present experiments, it was found that addition of physiologic concentrations of urea to the culture medium is able to restrain the action of aldosterone in embryonic CD epithelia. Urea antagonizes in a concentration-dependent manner the action of aldosterone finally leading to only 10% of PNA-binding cells. The data point to a urea-specific effect, because osmolytes such as NaCl and mannitol did not affect PNA binding. In addition, urea did not influence expression of principal-cell typical markers such as AQP2 and 3. The findings may explain that a higher number of PNA-positive cells is found in the cortical region of the kidney correlated with a low concentration of urea as compared with only few PNA-binding cells in the medullary CD, where a high concentration of urea occurs. Thus, an increasing concentration of urea may trigger the number of PNA-positive cells in the cortical-medullary course of the CD during organ development. E-mail: karl.schumacher@vkl.uni-regensburg.de
Gene Expression Profiles of Podocyte-Associated Molecules as Diagnostic Markers in Acquired Proteinuric Diseases
Authors: Schmid Holger , Henger Anna , Cohen Clemens D. , Frach Karin , Gröne Hermann-Josef , Schlöndorff Detlef , Kretzler Matthias 
Published: October 2004

ABSTRACT.
For identifying potential diagnostic markers of proteinuric glomerulopathies, glomerular mRNA levels of molecules relevant for podocyte function (α-actinin-4, glomerular epithelial protein 1, Wilms tumor antigen 1, synaptopodin, dystroglycan, nephrin, podoplanin, and podocin) were determined by quantitative real-time RT-PCR from microdissected glomeruli. Biopsies from 83 patients with acquired proteinuric diseases were analyzed (minimal change disease [MCD; n = 13], benign nephrosclerosis [n = 16], membranous glomerulopathy [n = 31], focal and segmental glomerulosclerosis [FSGS; n = 9], and controls [n = 14]). Gene expression levels normalized to two different housekeeping transcripts (glyceraldehyde-3-phosphate-dehydrogenase and 18 S rRNA) did not allow a separation between proteinuric disease categories. However, a significant positive correlation between α-actinin-4, glomerular epithelial protein 1, synaptopodin, dystroglycan, Wilms tumor antigen 1, and nephrin was found in all analyzed glomeruli, whereas podocin mRNA expression did not correlate. Because varying amounts of housekeeper cDNA per glomerulus can confound expression ratios relevant for a subpopulation of cells, an “in silico” microdissection was performed using a podocyte-specific cDNA as a reference gene. Expression ratio of podocin to synaptopodin, the two genes with the most disparate expression, allowed a robust separation of FSGS from MCD and nephrosclerosis. Segregation of FSGS from MCD via this ratio was confirmed in an independent population of formaldehyde-fixed archival biopsies (MCD, n = 5; FSGS, n = 4) after glomerular laser capture microdissection. In addition, the expression marker was able to predict steroid responsiveness in diagnostically challenging cases of MCD versus FSGS (n = 6). As the above approach can be performed as an add-on diagnostic tool, these molecular diagnostic parameters could give novel information for the management of proteinuric diseases. E-mail: kretzler@medpoli.med.uni-muenchen.de
Role of Oxidative Stress in Endothelial Dysfunction and Enhanced Responses to Angiotensin II of Afferent Arterioles from Rabbits Infused with Angiotensin II
Authors: Wang Dan , Chen Yifan , Chabrashvili Tina , Aslam Shakil , Borrego Conde Lillian J. , Umans Jason G. , Wilcox Christopher S. 
Published: October 2004

ABSTRACT.
The hypothesis that O2
·− enhances angiotensin II (AngII)-induced vasoconstriction and impairs acetylcholine-induced vasodilation of afferent arterioles (Aff) in AngII–induced hypertension was investigated. Rabbits (n = 6 per group) received 12 to 14 d of 0.154 M NaCl (Sham), subpressor AngII (60 ng/kg per min; AngII 60) or slow pressor AngII (200 ng/kg per min; AngII 200). Individual Aff were perfused in vitro at 60 mmHg. AngII 200 increased mean arterial pressure (mean ± SD; 103 ± 9 versus 73 ± 6 mmHg; P < 0.01), plasma lipid peroxides (2.6 ± 0.3 versus 2.0 ± 0.3 nM; P < 0.05), renal cortical NADPH- and NADH-dependent O2
·− generation, and Aff mRNA for p22phox 5-fold (P < 0.001) but decreased that for AT1-receptor 2.4-fold (P < 0.01). AngII 60 increased only NADH-dependent O2
·− generation by renal cortex. Aff from AngII 200 rabbits had diminished acetylcholine relaxations (+50 ± 4 versus +85 ± 6%; P < 0.001), but these became similar in the presence of nitro-L-arginine (10−4 M). Aff from AngII 60 and AngII 200 rabbits had unchanged norepinephrine contractions (10−7 M) but significantly (P < 0.05) enhanced AngII contractions (10−8 M: Sham −52 ± 5 versus AngII 60 to 77 ± 5 versus AngII 200 to 110 ± 10%). The superoxide dismutase mimetic tempol (10−4 M) moderated the AngII responses of Aff from AngII 200 rabbits to levels of AngII 60 rabbits (−64 ± 7%). The AngII slow pressor response enhances renal cortical O2
·− and p22phox expression. Increased O2
·− generation in Aff mediates an impaired nitric oxide synthase–dependent endothelium-derived relaxing factor response and paradoxically enhances contractions to AngII despite downregulation of the mRNA for AT1 receptors. A subpressor dose of AngII enhances Aff responses to AngII independent of O2
·−. E-mail: wilcoxch@georgetown.edu
Obesity Is Associated with Worse Peritoneal Dialysis Outcomes in the Australia and New Zealand Patient Populations
Authors: McDonald Stephen P. , Collins John F. , Johnson David W. 
Published: October 2004

ABSTRACT.
Although obesity is associated with increased risks of morbidity and death in the general population, a number of studies of patients undergoing hemodialysis have demonstrated that increasing body mass index (BMI) is correlated with decreased mortality risk. Whether this association holds true among patients treated with peritoneal dialysis (PD) has been less well studied. The aim of this investigation was to examine the association between BMI and outcomes among new PD patients in a large cohort, with long-term follow-up monitoring. Using data from the Australia and New Zealand Dialysis and Transplant Registry, an analysis of all new adult patients (n = 9679) who underwent an episode of PD treatment in Australia or New Zealand between April 1, 1991, and March 31, 2002, was performed. Patients were classified as obese (BMI of ≥30 kg/m2), overweight (BMI of 25.0 to 29.9 kg/m2), normal weight (BMI of 20 to 24.9 kg/m2), or underweight (BMI of <20 kg/m2). In multivariate analyses, obesity was independently associated with death during PD treatment (hazard ratio, 1.36; 95% confidence interval, 1.14 to 1.54; P < 0.05) and technique failure (hazard ratio, 1.17; 95% confidence interval, 1.07 to 1.26; P < 0.01), except among patients of New Zealand Maori/Pacific Islander origin, for whom there was no significant relationship between BMI and death during PD treatment. A supplementary fractional polynomial analysis modeled BMI as a continuous predictor and indicated a J-shaped relationship between BMI and patient mortality rates and a steady increase in death-censored technique failure rates up to a BMI of 40 kg/m2; the mortality risk was lowest for BMI values of approximately 20 kg/m2. In conclusion, obesity at the commencement of renal replacement therapy is a significant risk factor for death and technique failure. Such patients should be closely monitored during PD and should be considered for early transfer to an alternative renal replacement therapy if difficulties are experienced. E-mail: stephenm@ anzdata.org.au
Genetic Variation in the Renin-Angiotensin System and Progression of Diabetic Nephropathy
Authors: Jacobsen Peter , Tarnow Lise , Carstensen Bendix , Hovind Peter , Poirier Odette , Parving Hans-Henrik 
Published: October 2004

ABSTRACT.
The impact of polymorphisms in the genes coding for angiotensinogen (M235T), ACE (ID), and angiotensin II type 1 receptor (A
1166→C) on decline in GFR and doubling of s-creatinine or development of ESRD in patients with type 1 diabetes and diabetic nephropathy (DN) was tested. From 1985, all patients (n = 169) who had established diabetic nephropathy and were treated with angiotensin-converting enzyme inhibition (ACE-I) were identified consecutively at Steno Diabetes Center. Patients were followed for a median of 6 yr (range, 3 to 15 yr), with nine (range, three to 29) measurements of GFR (51Cr-EDTA). In a Cox proportional hazards model corrected for other risk factors, the D allele (ACE/ID) was associated with time to doubling of s-creatinine/ESRD (rate ratio, 1.81 per allele; 95% confidence interval, 1.09 to 3.03; P = 0.02). A new interaction hypothesis was generated demonstrating that the following variables were associated with accelerated decline in GFR: albuminuria (estimate, 2.12 ml/min per yr per 10-fold increase in albuminuria; P < 0.001), mean BP (estimate, 0.88 ml/min per yr per 10 mmHg; P = 0.02), hemoglobin A1c (estimate, 0.54 min/min per yr per 1%; P = 0.02), and number of M (M235T)/D (ID)/A (A
1166→C) alleles (estimate, 0.45 ml/min per yr per allele; P = 0.049). Number of M/D/A alleles also influenced time to doubling of s-creatinine or ESRD. In this study of patients with type 1 diabetes, the D allele of the ACE/ID polymorphism in addition to nongenetic risk factors independently accelerated progression of DN during ACE-I. Interaction between polymorphisms in the renin-angiotensin system also influenced the loss of kidney function. This new genetic interaction model needs to be confirmed in future studies. E-mail: pkjacobsen@dadlnet.dk
A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin
Authors: Dahan Karin , Devuyst Olivier , Smaers Michèle , Vertommen Didier , Loute Guy , Poux Jean-Michel , Viron Béatrice , Jacquot Christian , Gagnadoux Marie-France , Chauveau Dominique , Büchler Mathias , Cochat Pierre , Cosyns Jean-Pierre , Mougenot Béatrice , Rider Mark H. , Antignac Corinne , Verellen-Dumoulin Christine , Pirson Yves 
Published: October 2004

ABSTRACT.
Familial juvenile hyperuricemic nephropathy (FJHN [MIM 162000]) is an autosomal-dominant disorder characterized by abnormal tubular handling of urate and late development of chronic interstitial nephritis leading to progressive renal failure. A locus for FJHN was previously identified on chromosome 16p12 close to the MCKD2 locus, which is responsible for a variety of autosomal-dominant medullary cystic kidney disease (MCKD2). UMOD, the gene encoding the Tamm-Horsfall/uromodulin protein, maps within the FJHN/MCKD2 critical region. Mutations in UMOD were recently reported in nine families with FJHN/MCKD2 disease. A mutation in UMOD has been identified in 11 FJHN families (10 missense and one in-frame deletion)—10 of which are novel—clustering in the highly conserved exon 4. The consequences of UMOD mutations on uromodulin expression were investigated in urine samples and renal biopsies from nine patients in four families. There was a markedly increased expression of uromodulin in a cluster of tubule profiles, suggesting an accumulation of the protein in tubular cells. Consistent with this observation, urinary excretion of wild-type uromodulin was significantly decreased. The latter findings were not observed in patients with FJHN without UMOD mutations. In conclusion, this study points to a mutation clustering in exon 4 of UMOD as a major genetic defect in FJHN. Mutations in UMOD may critically affect the function of uromodulin, resulting in abnormal accumulation within tubular cells and reduced urinary excretion. E-mail: Dahan@gmed.ucl.ac.be
Molecular Analysis of the SGLT2 Gene in Patients with Renal Glucosuria
Authors: Santer René , Kinner Martina , Lassen Christoph L. , Schneppenheim Reinhard , Eggert Paul , Bald Martin , Brodehl Johannes , Daschner Markus , Ehrich Jochen H.H. , Kemper Markus , Li Volti Salvatore , Neuhaus Thomas , Skovby Flemming , Swift Peter G.F. , Schaub Jürgen , Klaerke Dan 
Published: October 2004

ABSTRACT.
The role of SGLT2 (the gene for a renal sodium-dependent glucose transporter) in renal glucosuria was evaluated. Therefore, its genomic sequence and its intron-exon organization were determined, and 23 families with index cases were analyzed for mutations. In 21 families, 21 different SGLT2 mutations were detected. Most of them were private; only a splice mutation was found in 5 families of different ethnic backgrounds, and a 12-bp deletion was found in two German families. Fourteen individuals (including the original patient with ’renal glucosuria type 0′) were homozygous or compound heterozygous for an SGLT2 mutation resulting in glucosuria in the range of 14.6 to 202 g/1.73 m2/d (81 - 1120 mmol/1.73 m2/d). Some, but not all, of their heterozygous family members had an increased glucose excretion of up to 4.4 g/1.73 m2/d (24 mmol/1.73 m2/d). Likewise, in index cases with glucosuria below 10 g/1.73 m2/d (55 mmol/1.73 m2/d) an SGLT2 mutation, if present, was always detected in the heterozygous state. We conclude that SGLT2 plays an important role in renal tubular glucose reabsorption. Inheritance of renal glucosuria shows characteristics of a codominant trait with variable penetrance. E-mail: r.santer@uke.uni-hamburg.de
Hypoxia-Inducible Factors and Kidney Vascular Development
Authors: Freeburg Paul B. , Abrahamson Dale R. 
Published: October 2004

ABSTRACT.
Among the genes strongly induced by hypoxia-inducible factors (HIF) and highly expressed during kidney microvascular development is vascular endothelial growth factor, which encodes a potent endothelial mitogen and chemoattractant critical for embryonic vasculogenesis and angiogenesis. In developing kidney, glomerular podocytes are particularly rich sources of vascular endothelial growth factor, which probably serves to attract endothelial precursors into vascular clefts of immature glomeruli, promote their mitosis and differentiation into glomerular endothelial cells, and assist with maintenance of their highly differentiated state through maturation. This article summarizes the structure, function, and expression of HIF and discusses HIF target genes expressed during kidney vascular development. Furthermore, it is speculated that different HIF heterodimers are stabilized in different cell populations, which may lead to cell-selective induction of HIF target genes important for renal vasculogenesis/angiogenesis. E-mail: dabrahamson@kumc.edu
Inhibition of Erythrocyte Cation Channels by Erythropoietin
Authors: Myssina Svetlana , Huber Stephan M. , Birka Christina , Lang Philipp A. , Lang Karl S. , Friedrich Björn , Risler Teut , Wieder Thomas , Lang Florian 
Published: October 2004

ABSTRACT.
Recombinant human erythropoietin therapy is used to counteract anemia that is the result of renal insufficiency. It stimulates the formation of peripheral blood erythrocytes by inhibiting apoptosis of erythrocyte precursor cells. Mature erythrocytes have similarly been shown to undergo apoptosis. Hyperosmotic shock and Cl− removal activate a Ca2+-permeable, ethylisopropylamiloride-inhibitable cation channel. The subsequent increase of cytosolic Ca2+ activates a scramblase that breaks down cell membrane phosphatidylserine asymmetry, leading to annexin binding. Studied was whether channel activity and erythrocyte cell death are regulated by erythropoietin. Scatchard plot analysis disclosed low-abundance, high-affinity binding of 125I-erythropoietin to erythrocytes. Whole cell patch clamp experiments revealed significant inhibition of the ethylisopropylamiloride-sensitive current by 1 U/ml erythropoietin. Cl− removal triggered annexin binding, an effect abrogated by erythropoietin (1 U/ml) but not by GM-CSF (10 ng/ml). Osmotic shock (700 mOsm) stimulated annexin binding within 24 h in the majority of the erythrocytes, an effect blunted by erythropoietin (1 U/ml) but not by GM-CSF (10 ng/ml). In the nominal absence of Ca2+, the effect of osmotic shock was blunted and the effect of erythropoietin abolished. In hemodialysis patients, intravenous administration of erythropoietin (50 IU/kg) within 4 h decreased the number of annexin binding circulating erythrocytes. Erythropoietin binds to erythrocytes and inhibits volume-sensitive erythrocyte cation channels and thus the breakdown of phosphatidylserine asymmetry after activation of this channel. The effect could prolong the erythrocyte lifespan and may contribute to the enhancement of the erythrocyte number during erythropoietin therapy in dialysis patients. E-mail: florian.lang@uni-tuebingen.de
Impaired Renal Secretion of Substrates for the Multidrug Resistance Protein 2 in Mutant Transport–Deficient (TR−) Rats
Authors: Masereeuw Rosalinde , Notenboom Sylvia , Smeets Pascal H. E. , Wouterse Alfons C. , Russel Frans G. M. 
Published: October 2004

ABSTRACT.
Previous studies with mutant transport–deficient rats (TR−), in which the multidrug resistance protein 2 (Mrp2) is lacking, have emphasized the importance of this transport protein in the biliary excretion of a wide variety of glutathione conjugates, glucuronides, and other organic anions. Mrp2 is also present in the luminal membrane of proximal tubule cells of the kidney, but little information is available on its role in the renal excretion of xenobiotics. The authors compared renal transport of the fluorescent Mrp2 substrates calcein, fluo-3, and lucifer yellow (LY) between perfused kidneys isolated from Wistar Hannover (WH) and TR− rats. Isolated rat kidneys were perfused with 100 nM of the nonfluorescent calcein-AM or 500 nM fluo3-AM, which enter the tubular cells by diffusion and are hydrolyzed intracellularly into the fluorescent anion. The urinary excretion rates of calcein and fluo-3 were 3 to 4 times lower in perfused kidneys from TR− rats compared with WH rats. In contrast, the renal excretion of LY (10 μM, free anion) was somewhat delayed but appeared unimpaired in TR− rats. Membrane vesicles from Sf9 cells expressing human MRP2 or human MRP4 indicated that MRP2 exhibits a preferential affinity for calcein and fluo-3, whereas LY is a better substrate for MRP4. We conclude that the renal clearance of the Mrp2 substrates calcein and fluo-3 is significantly reduced in TR− rat; for LY, the absence of the transporter may be compensated for by (an)other organic anion transporter(s). E-mail: R.Masereeuw@ncmls.kun.nl