endothelin-1 and Polycystic-Kidney--Autosomal-Dominant

Endothelin-1 (ET-1) is associated with the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD) via cyst progression. Elevated concentrations of ET-1 in ADPKD correlate with many phenotypic changes in the kidney such as renal cyst development, interstitial fibrosis, and glomerulosclerosis. In addition, an imbalance between renal ET. PubMed/Medline, Embase, and Google Scholar databases were searched using the key words "endothelin, endothelin-1 antagonists, and autosomal dominant polycystic kidney disease". All animal and human studies describing the effects of endothelin and endothelin-1 antagonists in ADPKD subjects were included in the review.. Urinary ET-1 concentrations could serve as a noninvasive surrogate biomarker for kidney ET-1 levels, as it is inversely associated with eGFR, independent of age, sex, and blood pressure. Elevated urinary excretion of ET-1 may be a biomarker for early renal injury. Antagonization of ET-1 may hopefully be a novel therapy for slowing progression of kidney damage in ADPKD.. Based on the literature reviewed in this manuscript, it is proposed that further research evaluating the efficacy of endothelin antagonists in treatment of cystic kidney disease is warranted. More human studies need to be performed with larger sample sizes. Therefore, the recommendation for treatment is inconclusive at this time.
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Topics: Animals; Biomarkers; Disease Progression; Endothelin-1; Glomerular Filtration Rate; Humans; Polycystic Kidney, Autosomal Dominant

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease in man and is caused by germline mutations in PKD1 or PKD2. Affected patients develop progressively enlarged kidneys due to the growth of multiple renal epithelial cysts. Several studies have demonstrated marked intrafamilial phenotypic variability in PKD1 or PKD2 pedigrees, indicating the importance of nonallelic factors such as genetic modifying loci in determining individual phenotype. Endothelin (ET)-1 exerts multiple and often opposing effects on different aspects of renal physiology through its major ET receptor subtypes, ET(A) and ET(B). Recent studies have reported that EDN1 and EDNRA polymorphisms can influence the age of onset of end-stage renal disease in ADPKD. Both circulating and local ET-1 systems are abnormally activated in human disease and experimental models, and ET(A) receptor expression is specifically upregulated in human ADPKD kidneys. Overexpression of ET-1 in transgenic mice is sufficient to trigger cyst initiation. However, studies utilizing selective ET(A) and ET(B) receptor antagonists to delay cystic disease progression in rodent PKD models have proved disappointing and do not support further extension into clinical trials. A critical balance between ET(A) and ET(B) action in the cystic kidney appears to be necessary to maintain kidney structure and function. Current evidence suggests that ET-1 and its receptors act as major modifying genes for renal disease progression in ADPKD. The future challenge will be to translate these findings to modify disease severity or for predicting prognosis in man.

Topics: Animals; Cell Proliferation; Endothelin-1; Humans; Hypertension; Kidney Tubules; Polycystic Kidney, Autosomal Dominant; Polymorphism, Single Nucleotide; Receptor, Endothelin A

Endothelin-1 (ET-1) is potent vasoconstrictive peptide and elevated ET-1 levels are associated with hypertension, endothelial dysfunction and atherosclerosis. Research on (ET-1) has demonstrated that elevated ET-1 levels in autosomal dominant polycystic kidney disease leads to systemic hypertension. The prevalence of simple renal cysts increases with age and the association with simple renal cyst and hypertension is not clear. The aim of this study was to investigate the ET-1 levels in patients with simple renal cyst and compare them with those in healthy adults.. The study included patients that underwent laparoscopic renal cyst decortication in the Department of Urology and healthy controls. Serum and urinary ET-1 levels were measured before surgery and one month after it in the patients with simple renal cyst. Serum ET-1 levels were measured in healthy adult patients. Ambulatory blood pressure was measured in all patients. Glomerular filtration rate was measured according to the chronic kidney disease epidemiology collaboration formula.. Thirty-two patients were included in the present study. Of these, 16 patients with simple renal cyst were allocated into group 1 and 16 healthy patients - in group 2. There was no significant difference between systolic and diastolic blood pressure between the groups (.. The present study demonstrated that serum EL-1 level in patients with simple renal cyst was lower than that in healthy people. Further studies are needed to investigate the EL-1 levels in simple renal cyst patients.

Topics: Aged; Endothelin-1; Female; Humans; Laparoscopy; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Prospective Studies

The prominent features of autosomal dominant polycystic kidney disease (ADPKD) are early development of hypertension, chronic kidney disease and cardiovascular problems. Thus, we aimed to investigate the role of endothelin, a vascular biomarker, in the clinical course of ADPKD, including renal and cardiovascular survival.. In 138 patients with ADPKD and 28 healthy controls, we measured serum endothelin-1 (ET-1) levels by enzyme-linked immunosorbent assay (ELISA). Endothelium-dependent vasodilatation (flow-mediated dilatation, FMD) and endothelium-independent vasodilatation (nitroglycerin-mediated dilatation, NMD) of the brachial artery were assessed non-invasively with high-resolution ultrasound. Magnetic resonance imaging (MRI) was performed with a 1.5-T system, and total kidney volumes were calculated using mid-slice technique. To determine PKD1 and PKD2 genotype, we performed molecular and genetic tests involving the following steps: DNA isolation, next-generation sequencing (NGS) and data analysis.. Endothelin levels and height-adjusted total kidney volumes (hTKV) significantly increased while the estimated glomerular filtration rate (eGFR) decreased across CKD stages 1-4. Hypertension was more frequent in ADPKD patients with high serum endothelin. At multivariate Cox analysis, endothelin level, PKD1 truncating mutation, hTKV, high-sensitive C reactive protein (hs-CRP) level and the presence of diabetes mellitus were associated with the risk of overall survival. Moreover, endothelin level, PKD1 truncating mutation, hTKV, age and presence of hypertension were associated with the risk of renal survival. Additionally, body mass index (BMI), FMD, PKD1 truncating mutation, endothelin and triglyceride levels were independently associated with hypertension.. Increased serum endothelin levels independently predict hypertension in ADPKD. Serum endothelin levels are also associated with both renal and overall survival in patients with ADPKD.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; Disease Progression; Endothelin-1; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Kidney; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Prognosis; Renal Insufficiency, Chronic; Risk Factors; Time Factors; Up-Regulation

The pathogenesis of progressive renal insufficiency in autosomal dominant polycystic kidney disease (ADPKD) is unclear. Evidence from experimental models of ADPKD suggests that elevated endothelin-1 (ET-1) drives cyst growth, renal fibrosis and loss of renal function, but whether ET-1 is elevated in humans with ADPKD is uncertain.. In a cross-sectional study of ADPKD we measured urinary ET-1, a surrogate for ET-1 in kidney cortex, in spot collections corrected for creatinine. The volume of each kidney was measured using MRI-based stereology. The relationship of urine ET-1 with MDRD eGFR and kidney volume was modeled by multiple linear regression with adjustment for clinical covariates.. Patients with ADPKD were ages 18 to 53 with eGFRs (median, interquartile range) of 63.2 (43.5-80.2) ml/min/1.73 m(2) and albumin/creatinine ratios (ACR) of 115.0 (7.5-58.5) μg/mg. Urine ET-1 was inversely associated with eGFR (r = -0.480, P < 0.05) and positively (r = 0.407, P = 0.066) with ACR independent of age and female sex (P < 0.01). ET-1 appeared to be positively associated with total kidney volume (r = 0.426, P = 0.100), with a test for trend across urine ET-1 quartiles yielding z = 1.83, P = 0.068. ET-1 strongly correlated with NAGase (r = 0. 687, P = 0.001), a marker of tubular damage and a surrogate marker of renal disease progression in ADPKD. Of note, ET-1 levels in urine were not correlated with hypertension.. In a translational study of patients with ADPKD, urinary ET-1 was inversely associated with eGFR and positively correlated with total kidney volume. Taken together with results from experimental models, these findings suggest that the role of ET-1 in ADPKD warrants further investigation.

Topics: Acetylglucosaminidase; Adolescent; Adult; Cross-Sectional Studies; Disease Progression; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Magnetic Resonance Imaging; Male; Middle Aged; Organ Size; Pilot Projects; Polycystic Kidney, Autosomal Dominant; Renal Insufficiency; Severity of Illness Index; Young Adult

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease that causes kidney failure and accounts for 10% of all patients who are on renal replacement therapy. However, the marked phenotypic variation between patients who carry the same PKD1 or PKD2 mutation suggests that nonallelic factors may have a greater influence on the cystic phenotype. Endothelin-1 (ET-1) transgenic mice have been reported to develop profound renal cystic disease and interstitial fibrosis without hypertension. The hypothesis that ET-1 acts as a modifying factor for cystic disease progression was tested in an orthologous mouse model of ADPKD (Pkd2(WS25/-)). Four experimental groups (n = 8 to 11) were treated from 5 to 16 wk of age with the highly selective orally active receptor antagonists ABT-627 (ETA) and A-192621 (ETB) singly or in combination. Unexpected, ETB blockade led to accelerated cystic kidney disease. Of significance, this was associated with a reduction in urine volume and sodium excretion and increases in urine osmolarity and renal cAMP and ET-1 concentrations. The deleterious effect of chronic ETB blockade was neutralized by simultaneous ETA blockade. ETA blockade alone resulted in a significant increase in tubular cell proliferation but did not alter the cystic phenotype. It is concluded that the balance between ETA and ETB signaling is critical for maintaining tubular structure and function in the cystic kidney. These results implicate ET, acting via vasopressin-dependent and independent pathways, as a major modifying factor for cystic disease progression in human ADPKD.

Topics: Animals; Crosses, Genetic; Disease Models, Animal; Disease Progression; Endothelin B Receptor Antagonists; Endothelin-1; Fibrosis; Humans; Mice; Polycystic Kidney, Autosomal Dominant; Vasoconstrictor Agents; Viper Venoms

A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). The variability cannot be fully explained by the genetic heterogeneity of the disease. Endothelin-1 (ET-1) has been suggested to be a major promoting factor in renal diseases. The role of the ET-1 gene locus (EDN1) in the renal function in the general nondiabetic population was evaluated. We examined the influence of three single-nucleotide polymorphisms of the ET-1 gene (EDN1)--K198N, 3A/4A, and T-1370G--on the progression of ADPKD towards end-stage renal disease (ESRD).. Two hundred and five ADPKD patients (113 males and 92 females) who had reached ESRD were analyzed. The patients were divided into three groups: (1) 48 patients (23 males and 25 females) with ESRD later than 63 years of age (slow progressors), (2) 74 patients (41 males and 33 females) with ESRD before 45 years of age (rapid progressors), and (3) 83 patients (49 males and 34 females) with ESRD between 45 and 63 years old. DNA samples from collected blood were genotyped for three single-nucleotide polymorphisms of EDN1: K198N, 3A/4A, and T-1370G. Haplotype analysis was also done in 200 healthy individuals. We compared the frequencies of the different genotypes between the groups of slow and rapid progressors and the ages at the time of ESRD regarding the EDN1 genotypes.. The EDN1 genotype distribution showed no differences among the groups of slow progressors, rapid progressors, the ADPKD group with ESRD between 45 and 63 years old, and the control group. Comparing the ages of ESRD of all patients, we did not find significant differences with regard to the different genotypes. Furthermore, we compared the combinations of the different haplotypes and the ages at the time of ESRD. We found no differences in ages at the time of ESRD in patients with different haplotypes in the endothelin promoter (T-1370G) in combination with 3A/4A or K198N polymorphisms. Comparing the ages at the time of ESRD in patients with different 3A/4A and K198N haplotypes, we found a significantly lower age at the time of ESRD (47.1 +/- 8.7 years) in the carriers of the 4A allele in combination with the 198N allele (4A/4A, 3A/4A + 198KN,NN) than in the carriers of the 4A allele homozygous for the K198 allele (52.9 +/- 10.9 years; 4A/4A, 3A/4A + 198KK; t test: p < 0.01) and in the carriers of the 198N allele homozygous for the 3A allele (53 +/- 11.2 years; 3A/3A + 198KN,NN; t test: p < 0.05).. We excluded an effect of K198N, 3A/4A, and T-1370G polymorphisms of EDN1 on the progression of ADPKD. However, a deleterious effect of the combination of 4A and 198N alleles of EDN1 was observed in APKDK individuals.

Topics: Aged; Chi-Square Distribution; Disease Progression; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Point Mutation; Polycystic Kidney, Autosomal Dominant; Polymorphism, Single Nucleotide

Male gender is a risk factor for progression of autosomal-dominant polycystic kidney disease (ADPKD), clinically and in the Han:SPRD rat model. Orchiectomy limits progression, but mechanisms of the detrimental effect of androgen, and/or beneficial effects of estrogen, are not known. This protocol tested the hypothesis that male gender (intact androgen status) promotes progression, while female gender (intact estrogen status) is protective; and that these disease-modifying effects are due to changes in expression of known fibrotic mediators.. Studies were performed in male and female noncystic control (+/+) and cystic (+/-) rats subjected to orchiectomy, ovariectomy, or sham operation. At 12 weeks of age, renal function was measured. Blood and kidneys were taken for measurement of plasma and renal renin, endothelin (ET-1), endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF), using biochemical, protein expression, and immunohistochemical methods.. Cystic male rats exhibited significantly reduced glomerular filtration (GFR) and effective renal plasma flow (ERPF) rates, with suppression of plasma and renal renin, up-regulation of renal ET-1 and eNOS, and down-regulation of renal VEGF expression. Orchiectomy attenuated the fall in GFR and ERPF, while numerically limiting changes in eNOS and VEGF. Female rats exhibited less cystic growth, with normal renin status, lesser elevation of renal ET-1, and proportionately lesser changes in VEGF and eNOS. Ovariectomy led to higher blood pressure and reduced GFR and ERPF, with a trend toward upregulation of ET-1, and significant down-regulation of VEGF and eNOS.. Female gender is protective, but ovariectomy attenuates the protective effect of female gender, in association with changes in renal expression of ET-1, VEGF, and eNOS. The accelerated disease in male rats can be attenuated by orchiectomy and consequent changes in expression of disease mediators.

Topics: Androgens; Animals; Body Weight; Endothelin-1; Estrogens; Female; Fibrosis; Kidney; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Orchiectomy; Organ Size; Ovariectomy; Polycystic Kidney, Autosomal Dominant; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Renin-Angiotensin System; Vascular Endothelial Growth Factor A

The major factors influencing the rate of progression of chronic renal disease in autosomal-dominant polycystic kidney disease (ADPKD) are unknown and there are currently no effective treatments for slowing the progression of chronic renal failure in ADPKD patients. As a first step in investigating the potential role of endothelin-1 (ET1) and its receptors (ETA and ETB) in the pathophysiology of progression in ADPKD, we have studied their expression and cellular localisation in ADPKD kidney. Immunoreactive ET1 was detected in cyst epithelia, mesangial cells and vascular smooth muscle cells suggesting continuing ET1 synthesis in the cystic kidney. Compared to healthy controls, ETA mRNA was 5-10-fold higher in ADPKD cystic kidney. In cystic kidney, neo-expression of ETA receptors was found overlying glomeruli and cysts and markedly increased in medium-sized renal arteries by microautoradiography. This is the first study to demonstrate a specific upregulation of ETA receptors in human renal disease. Future studies should address whether ETA selective antagonists may be effective in slowing renal disease progression in ADPKD.

Topics: Aged; Disease Progression; Endothelin-1; Female; Gene Expression Regulation; Glomerular Mesangium; Humans; Kidney Diseases, Cystic; Kidney Glomerulus; Kidney Tubules; Male; Middle Aged; Muscle, Smooth, Vascular; Nephrectomy; Organ Specificity; Polycystic Kidney, Autosomal Dominant; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by hypertension and renal vasoconstriction. Mediators of these hemodynamic changes are not well understood, but evidence suggests that endothelial-derived mediators may participate.. Baseline measurements of blood pressure, proteinuria, and urinary nitrite/nitrate excretion were performed in control and cystic male Han:SPRD rats (6 weeks of age). They were then treated with the nitric oxide (NO), nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), or vehicle, for 6 weeks. After repeat systemic measurements, renal function was determined using inulin and para-aminohippurate (PAH) clearances. Levels of renal endothelin-1 (ET-1) and renal endothelial NOS (eNOS) proteins were determined, and immunohistochemistry localized renal eNOS and neuronal NOS (nNOS).. Administration of L-NAME aggravated systemic hypertension and renal vasoconstriction in the cystic rats, but did not affect the progression of proteinuria or cystic expansion. Cystic rats demonstrated marked increases in renal ET-1 and eNOS levels. L-NAME reduced eNOS expression in the membrane compartment, but increased eNOS in the cytosol. Localization studies indicated that renal eNOS was abundant in nonvascular compartments, but not in renal vascular and glomerular structures, whereas renal nNOS was diffusely diminished.. These alterations of endothelial-derived mediators (up-regulation of ET-1, and dysfunction of the NO system) contribute to vasoconstriction, and thereby are likely to contribute to the progressive loss of renal function in polycystic kidney disease (PKD).

Topics: Animals; Blood Pressure; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Hypertension, Renal; Male; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitrites; Polycystic Kidney, Autosomal Dominant; Rats; Rats, Sprague-Dawley; Vasoconstriction

The pathogenesis of arterial hypertension in autosomal dominant polycystic kidney disease (ADPKD) is complex and likely dependent on interaction of hemodynamic, endocrine and neurogenic factors. We decided to evaluate the role of endothelin (ET1) and nitric oxide (NO) in the regulation of arterial blood pressure (BP) and to determine plasma levels of ET1 and NO in the group of patients with ADPKD. The ADPKD group (18 patients, 6 men + 12 women, mean age 44.6+/-11.7 years, with creatinine clearancecorrig > 1.1 ml/s) was compared with a control group of 27 healthy volunteers of comparable age. Plasma levels of ET1 assessed by direct RIA determination in the group of ADPKD patients (11.03+/-1.8 fmol/ml) were significantly increased (p<0.001) in comparison with the control group (2.66+/-0.58 fmol/ml), while no significant differences were observed between normotensive and hypertensive patients in the ADPKD group. Serum levels of NO were evaluated according to the determination of serum levels of their metabolites - nitrites/nitrates. Serum levels of NO in the group of ADPKD patients (39.85+/-.38 micro mol/l) were significantly higher (p<0.05) in comparison with the control group (22.7+/-1.20 micro mol/l), whereas in the ADPKD group no significant differences were observed between normotensive and hypertensive patients. Thus, our study supports the concept of complex alteration of both vasoconstrictor and vasodilator systems in the pathogenesis of arterial hypertension in ADPKD.

Topics: Adult; Aged; Antioxidants; Chronic Disease; Creatine; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Hypertension; Lipid Peroxidation; Male; Middle Aged; Nitric Oxide; Polycystic Kidney, Autosomal Dominant