endothelin-1 and Nephrotic-Syndrome

Endothelin-1 plays a crucial role in the pathophysiology of nephrotic syndrome (NS) in children. The primary purpose of this study is to evaluate the contribution of the EDN1 (3A/4A; rs1800997) variant to the risk of nephrotic syndrome. This study involves 200 participants (100 healthy controls, 50 steroid-sensitive nephrotic syndromes [SSNS] patients, and 50 steroid-resistant nephrotic syndromes [SRNS] patients]. Genomic DNA has been characterized using the PCR-RFLP technique. The predominant genotype that is common in this study population was the EDN1 3A/3A genotype (NS [75%] and healthy controls [88%]). The prevalence of EDN1 3A/4A genotype and EDN1 4A allele was significantly increased among NS patients compared with healthy subjects (p-value < 0.05). Furthermore, the frequency of the EDN1 (3A/4A; rs1800997) variant was statistically significant among SRNS patients (p-value < 0.05). The EDN1 3A/4A genotype and the EDN1 4A allele were identified as independent risk factors of the nephrotic syndrome among children.

Topics: 5' Untranslated Regions; Adolescent; Child; Child, Preschool; Endothelin-1; Female; Genetic Predisposition to Disease; Humans; Infant; Male; Nephrotic Syndrome; Polymorphism, Single Nucleotide

Primary nephrotic syndrome (NS) is a common glomerular disease in children. We assessed the genotypes and frequency of the rs5370 allelic variant of the EDN1 gene in children with primary NS.. We conducted a case-control study in Mansoura University Children's Hospital, Egypt between December 2015 and January 2018. We recruited 50 patients with steroid-sensitive NS (SSNS) and 50 patients with steroid-resistant NS (SRNS) in addition to 100 healthy controls. The patients underwent clinical evaluations and tests including measurement of serum albumin, cholesterol, creatinine and urea levels and a 24-h urinary protein test. We used polymerase chain reaction methods to assess the genotypes of rs5370 variants of the EDN1 gene (GG, GT and TT) and alleles (T and G) in the groups under study.. The most frequent genotype of the EDN1 gene at the locus of interest in the control group was the GT genotype (88%; P=.001) while the GG genotype was more frequent in the NS group compared to the control group (P=.02). We did not find statistically significant differences between the NS and control groups in regard to the EDN1 rs5370 alleles (P=.69). The GG genotype was more frequent in the SSNS group compared to the SRNS and control groups (P=.03). When we compared allele frequencies between the control, SSNS and SRNS groups, we did not find significant differences (P=.89). The GT genotype was associated with normal blood pressure in children with NS (P=.007), while the GG genotype was associated with hypertension (P<.001). We did not find statistically significant differences in renal histopathology or serum cholesterol levels based on the genotype.. The GG genotype at the rs5370 locus of the EDN1 gene may be associated with an increased risk of primary NS and a better response to steroid therapy.

Topics: Case-Control Studies; Child; Endothelin-1; Gene Frequency; Humans; Nephrotic Syndrome; Polymorphism, Genetic

Recently, the rs5370 single nucleotide polymorphisms (SNPs) of Endothelin-1 (EDN1) showed association with the susceptibility of childhood primary nephrotic syndrome (CPNS). This study aims to investigate potential relationships between other EDN1 SNPs and CPNS.. Seven SNPs (rs5370, rs10478723, rs1476046, rs1800541, rs2070698, rs2071942, and rs9296344) of the EDN1 gene were genotyped in 579 CPNS patients and 586 age-matched healthy children. Then, we analyzed potential associations of the six SNPs with susceptibility of CPNS by using rs5370 as a conditional variant in a logistic regression model. SNP-SNP interaction analysis was performed to investigate the joint effects of the seven SNPs in the pathogenesis of CPNS.. Independent with rs5370, only rs9296344 significantly associated (T vs C, odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.57-0.88, P = .001) with the susceptibility of CPNS. Meanwhile, no joint effect among the analyzed seven SNPs was discovered in this study.. This study discovered that C allele of rs9296344 on EDN1 is a novel independent risk factor for CPNS.

Topics: Alleles; Case-Control Studies; Child; Endothelin-1; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Linkage Disequilibrium; Male; Nephrotic Syndrome; Polymorphism, Single Nucleotide

BackgroundThe pathogenesis of idiopathic nephrotic syndrome (INS) remains unclear, although recent studies suggest endothelin 1 (ET-1) and CD80 of podocytes are involved. We investigated the potential of antagonist to ET-1 receptor type A (ETRA) as therapeutic agent through the suppression of CD80 in a rat model of INS.MethodsPuromycin aminonucleoside (PAN) was injected to Wister rats to induce proteinuria: some were treated with ETRA antagonist and others were treated with 0.5% methylcellulose. Blood and tissue samples were collected. Quantitative PCR was used to determine the expression of Toll-like receptor-3 (TLR-3), nuclear factor-κB (NF-κB), CD80, talin, ETRA, and ET-1 in the kidney. To confirm the level of CD80 protein expression, immunofluorescence staining and western blot analysis of the renal tissue were performed.ResultsAmount of proteinuria in the treatment group was significantly lower than the other groups. The same-day body weight, serum creatinine values, and blood pressure were not significantly different. ETRA antagonist restores podocyte foot process effacement as well as the aberrant expression of TLR-3, nuclear factor-κB (NF-κB), and CD80 in PAN-injured kidneys.ConclusionsThe ETRA antagonist may be promising drug for INS as it showed an antiproteinuric effect. Its action was considered to be through suppression of CD80 expression on podocytes.

Topics: Animals; B7-1 Antigen; Blood Pressure; Body Weight; Creatinine; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Female; Kidney; Kidney Diseases; Kidney Glomerulus; Nephrosis; Nephrotic Syndrome; NF-kappa B; Phenylpropionates; Podocytes; Proteinuria; Puromycin Aminonucleoside; Pyridazines; Rats; Rats, Wistar; Receptor, Endothelin A; Toll-Like Receptor 3

This study aims to investigate the relationship between plasma endothelin-1 (ET-1) concentrations, ET-1 gene polymorphisms in loci rs5370, rs1630736, 3A/4A and clinical features of primary nephrotic syndrome (NS) in children.. Thirty-six children with primary NS were selected as case group, and 94 healthy children were selected as control group. All subjects were genotyped for three single nucleotide polymorphisms (SNPs) (rs5370, rs10478694 [3A4A] and rs 1630736) in the ET-1 gene by gene sequencing. The plasma ET-1 concentrations were measured using a radio-immunoassay.. Plasma ET-1 concentrations were higher in NS patients (P=0.007) as compared to healthy children. The allele frequencies between control and NS patients were significantly different only with respect to the rs10478694 SNP of the ET-1 gene. The allele frequencies between control and NS patients for the rs5370 SNP showed a trend towards difference (P=0.057). Plasma cholesterol in NS patients is associated with both: the GT genotype in locus rs5370 and the 3A4A genotype in locus rs10478694 (P<0.05 in both cases).. The ET systems might play a disease modifying role in pediatric NS. Plasma cholesterol, a hallmark of NS, seems to be associated with genetic variations within the human ET-1 gene.

Topics: Blood Urea Nitrogen; Case-Control Studies; Child; Creatinine; Endothelin-1; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Male; Nephrotic Syndrome; Phenotype; Polymorphism, Single Nucleotide

Endothelin-1 (ET-1), which acts via the specific receptors ET-A and ET-B, has been implicated in the development of renal scarring. The activation of the endothelin system was observed in experimental models of glomerular diseases and was attributed to the toxic action of proteinuria on the tubular epithelial cells. The aim of this study was to investigate whether the endothelin system in the kidney is altered in glomerular diseases and possibly related to proteinuria.. Thirty-seven patients with different types of glomerulonephritis and 14 controls were included. Patients presented either nephrotic syndrome (n=25) or mild proteinuria (<1g/24h, n=12). The expression of ET-A and ET-B receptors in the renal tissue was examined immunohistochemically. At the time of biopsy, urinary ET-1 was determined.. Both receptors were mainly localized within tubular epithelial cells, and their expression was significantly higher in patients with glomerulonephritis compared to controls. The expression of ET-B was higher in nephrotic compared to non-nephrotic patients, while no difference was observed in the expression of ET-A receptors. A significant positive correlation of the degree of proteinuria with the excreted ET-1 (r= 0.487, p<0.05) and the extent of immunostaining for ET-B receptors (r=0.420, p<0.05) was observed. The expression of ET-B receptors and the excretion of ET-1 decreased significantly in patients with remission of nephrotic syndrome after therapy.. This study provides evidence that the endothelin system is activated in human glomerular disease, confirming data from experimental studies. Proteinuria seems to be related to the activation of endothelin system, though further investigation is necessary to clarify this issue.

Topics: Adult; Endothelin-1; Female; Fluorescent Antibody Technique, Indirect; Glomerulonephritis, IGA; Glomerulonephritis, Membranous; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Nephrosis, Lipoid; Nephrotic Syndrome; Proteinuria; Receptor, Endothelin A; Receptor, Endothelin B

Acute renal failure (ARF) occurs in some adult patients with minimal change nephropathy (MCN). To investigate clinical and pathological factors associated with developing ARF, we compared clinical features and kidney pathological characteristics of endothelin 1 (ET-1) expression in patients with adult-onset MCN with and without ARF.. The patient population consisted of 53 patients consecutively diagnosed with adult-onset MCN during a 10-year period. Based on creatinine clearance, 25 patients were assigned to the ARF group and 28 patients were assigned to the non-ARF group.. Clinical data show that the ARF group had a higher blood pressure, higher serum cholesterol level, and lower serum albumin level than the non-ARF group. Pathological data showed more severe foot-process effacement, interstitial edema, and flattened tubular epithelium in the same group. Greater ET-1 expression was detected in vessels, tubules, and glomeruli of the ARF compared with non-ARF group. The ARF group experienced a lower steroid response rate. However, there was no significant difference in stability of remission to steroid treatment in patients who achieved a remission.. ARF associated with enhanced kidney ET-1 expression is a reversible complication of MCN that occurs frequently in patients with apparently expanded extracellular fluid. Presumptively, ARF may develop as an amplification of the underlying pathogenesis of MCN involved in enhanced ET-1 expression, which may be superimposed by a transient episode of circulatory insufficiency during diuretic treatment.

Topics: Acute Kidney Injury; Adult; Age of Onset; Aged; Blood Pressure; Cholesterol; Cyclophosphamide; Diuretics; Edema; Endothelin-1; Epithelial Cells; Extracellular Fluid; Female; Humans; Kidney Glomerulus; Kidney Tubules; Male; Middle Aged; Nephrosis, Lipoid; Nephrotic Syndrome; Prednisolone; Remission Induction; Renal Circulation; Serum Albumin; Vasoconstriction

Nephrotic syndrome is characterized by severe proteinuria and sodium and water retention. Although endothelin (ET) 1 can cause natriuresis or antinatriuresis, the role played by ET-1 in proteinuria and in sodium retention due to nephrotic syndrome remains unclear.. We investigated the role played by the ET-1 system in sodium and water retention and in proteinuria in puromycin aminonucleoside induced nephrotic syndrome in rats using microdissected nephron segments, competitive polymerase chain reaction, and Western blot.. The expression of prepro ET-1, ET-converting enzyme 1 (ECE-1), and ET A receptor mRNAs, but not ET B receptor mRNA, in the glomeruli was increased in rats with nephrotic syndrome. The cGMP generation in the glomeruli induced by atrial natriuretic peptide and ET-1 was decreased, whereas the ET-3-induced cGMP generation was increased in rats with nephrotic syndrome. ECE-1 mRNA expression was increased not only in the glomeruli, but also in the thick ascending limbs and collecting ducts. The protein expression of ECE-1 was increased in the membrane fraction of the cortex and in the outer and the inner medulla of nephrotic rats. Blockade of ET A and B receptors by bosentan did not inhibit the occurrence of nephrotic syndrome. However, the administration of bosentan increased the urinary sodium excretion.. These data suggest that an activated ET-1-ET A receptor pathway in glomeruli and/or an increased ECE-1 mRNA expression in distal segments may participate in sodium and water retention, but not in the occurrence of nephrotic syndrome.

Topics: Animals; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Bosentan; Cyclic GMP; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Endothelin-Converting Enzymes; Enzyme Induction; Gene Expression Regulation, Enzymologic; Kidney Glomerulus; Male; Metalloendopeptidases; Nephrons; Nephrotic Syndrome; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sulfonamides; Time Factors

Topics: Adolescent; Adult; Endothelin-1; Female; Glomerulonephritis; Humans; Male; Middle Aged; Nephrotic Syndrome; Nitric Oxide

The effects of plasma endothelin-1 (ET-1) and aldosterone (Ald) on sodium retention in children with nephrotic syndrome were investigated. 14 cases were divided into the edematous stage and non-edematous stage. Plasma ET-1, Ald, and serum osmolarity, albumin (Alb), and Na+ were measured in each stage. The results showed that the plasma ET-1 in edemaous stage increased significantly, compared with that in no-edematous stage (P < 0.01). There was no significant difference in plasma Ald between the edematous stage and the non-edematous stage. Plasma ET-1 was positively correlated with the serum sodium ionic concentration and negatively correlated with the serum Alb(r = 0.486, P < 0.01; r = 0.490, P < 0.01, respectively). In conclusion, the sodium retention with nephrotic syndrome might be correlated with reduction of secreted sodium in the kidney, suggesting that ET-1 plays an important role in pathogenesis.

Topics: Aldosterone; Child; Child, Preschool; Endothelin-1; Female; Humans; Infant; Male; Nephrotic Syndrome; Sodium

Whether the serum levels of endothelin, a vasoconstrictive peptide produced in the endothelial cell, increase in preeclamptic patients is still controversial. We performed immunohistochemical studies to observe the changes in endothelin-1 (ET-1) in preeclamptic kidney tissues. The monoclonal anti-human ET-1 antibody (Yamasa, Japan) and anti-von Willebrand factor (vWF, Dako, Denmark), a marker of endothelial cells, were used for the studies by the strepto-avidin-biotin peroxidase method (ABC-POD Kit, Wako, Japan). Twenty-nine patients and 12 normal controls were divided into four groups. The preeclamptic group included 14 patients diagnosed with preeclampsia by clinical symptoms of hypertension, proteinuria, and edema occurring in late pregnancy and as having preeclamptic nephropathy. They underwent renal biopsy 16.7 +/- 1.0 (mean +/- SEM) days after delivery. The nephrotic group comprised 10 normotensive nonpregnant patients with nephrotic-range proteinuria examined through biopsy before treatment (six cases of minimal change, two of focal segmental glomerulosclerosis, one of membranous nephropathy, and one of IgA nephropathy). The pregnant women with preexisting glomerular disease group included five pregnant women with normal renal function who were normotensive and had no increase in the amount of proteinuria throughout pregnancy. They underwent renal biopsy 10.8 +/- 2.9 days after delivery (two cases of membranous nephropathy, one of focal segmental glomerulosclerosis, one of thin basement membrane disease, and one of non-IgA mesangioproliferative glomerulonephritis). The normal kidney group comprised 12 healthy tissue samples taken from nephrectomized kidneys (five cases of renal cell carcinoma, one case of lipofibrosarcoma, and six cases of kidney transplant donors). In these four groups, ET-1 and vWF showed equally positive staining in small arteries. VWF also showed positive staining in arterioles and peritubular capillaries in all groups. Although the glomeruli showed positive staining with ET-1 along the capillary walls in the normal group and the nonpregnant nephrotic group, they showed very weak or negative results in the preeclamptic group. Moreover, gravida with underlying glomerular disease without superimposed preeclampsia also showed negative findings of ET-1 in the glomeruli. The glomeruli in the four groups showed positive findings, with vWF readings the same as in the controls. These results indicate that the production of ET-1 in the

Topics: Adult; Analysis of Variance; Biopsy; Endothelin-1; Female; Glomerulonephritis; Humans; Immunoenzyme Techniques; Immunohistochemistry; Kidney; Middle Aged; Nephrotic Syndrome; Pre-Eclampsia; Pregnancy

Renal function is influenced by direct and indirect action of endothelins. They reduce renal blood flow and glomerular filtration. The aim of the present study was to determine plasma and urinary endothelin-1 (ET-1) in two major categories of renal patients and to compare them with normal subjects.. Endothelin-1 was measured in the plasma and urine of patients with chronic renal disease and reduced glomerular filtration rate (GFR), and in patients with proteinuria due to glomerular dysfunction with unaffected GFR. A group of healthy subjects was used as a reference.. Plasma endothelin-1 was increased in all patients to 60 +/- 13 pg/ml independent of GFR compared to 29 +/- 5 pg/ml in normal subjects (P < 0.001). The endothelin-1 load was decreased to 1190 +/- 450 pg/ml/1.73 m2 in patients with reduced GFR, compared to 2780 +/- 690 pg/ml/1.73 m2 of normal subjects, whereas in patients with glomerular damage and normal GFR, it was increased to 5480 +/- 1910 pg/ml/1.73 m2 (P < 0.01). ET-1 was found to be excreted and reabsorbed by the renal tubules by the same mechanisms as sodium and potassium, because its secretion fraction changes in parallel to those of the above ions. The excreted endothelin increased to 730 +/- 420 and 710 +/- 250 pg/ml/1.73 m2 (P < 0.01) in the two categories of patients respectively, compared to 290 +/- 100 pg/ml/1.73 m2 in the normal group. The excretion fraction of patients with normal GFR was similar to normal subjects, while it appeared to increase in patients with reduced GFR (P < 0.01).. In the development of renal disease the plasma endothelin concentration is independent of the renal filtration capability and endothelin may be involved in functional and anatomical changes of the kidney as a causal factor or resulting from the renal disease.

Topics: Adult; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Kidney; Male; Middle Aged; Nephrotic Syndrome