endothelin-1 and Renal-Insufficiency

Endothelial cells are essential regulators of vascular tone. They accomplish this by sensing humoral mediators and transducing their effects to the underlying vascular smooth muscle as well as by synthesizing vasoactive molecules that act in a paracrine fashion. In the kidney, the local release of these endothelial mediators, together with the concourse of specialized endothelial cells in the glomerulus, contribute to regulate renal blood flow, glomerular filtration, and tubular function that are intimately linked to sodium balance because they mutually influence each other. Ultimately, renal circulation and tubular function have a profound influence in systemic blood pressure as a result of the overall regulation of volume homeostasis.

Topics: Animals; Blood Pressure; Cyclic GMP; Endothelial Cells; Endothelin-1; Epoprostenol; Humans; Kidney; Nitric Oxide; Renal Circulation; Renal Insufficiency; Vasomotor System

NSF is a new and emerging disease. Significant investigative work to date has led to an unexpected suspect-gadolinium-containing contrast agents. Considerable additional work is now underway to formulate specific recommendations about the use of these agents in the population of patients who have renal disease. Goals on the immediate research horizon include (1) the identification of risk factors and conditions that must be met to permit the development of NSF in patients who have renal disease, (2) the characteristics of contrast agents that make them more or less likely to induce NSF, and (3) the development of prophylactic or treatment strategies that can reduce the overall development and severity of NSF. The investigative process has already yielded new insight into the functions (and malfunctions) of the CF in the setting of NSF. As the CF is being increasingly implicated in other organ-specific and systemic fibrosing disorders, we can expect to see significant developments in the studies of allied disorders as well.

Topics: Comorbidity; Contrast Media; Diagnosis, Differential; Endothelin-1; Fibrosis; Gadolinium; Gadolinium DTPA; Humans; Magnetic Resonance Imaging; Renal Insufficiency; Skin

Topics: Animals; Autocrine Communication; Endothelin-1; Humans; Hypertension; Kidney; Natriuresis; Paracrine Communication; Renal Circulation; Renal Insufficiency; Transcription Factors; Vasoconstriction

The endothelins are synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonal, and inflammatory cells. These peptides are converted by endothelin-converting enzymes (ECE-1 and -2) from 'big endothelins' originating from large preproendothelin peptides cleaved by endopeptidases. Endothelin (ET)-1 has major influence on the function and structure of the vasculature as it favors vasoconstriction and cell proliferation through activation of specific ET(A) and ET(B) receptors on vascular smooth muscle cells. In contrast, ET(B )receptors on endothelial cells cause vasodilation via release of nitric oxide (NO) and prostacyclin. Additionally, ET(B) receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Indeed, ET-1 contributes to the pathogenesis of important disorders as arterial hypertension, atherosclerosis, and heart failure. In patients with atherosclerotic vascular disease (as well as in many other disease states), ET-1 levels are elevated and correlate with the number of involved sites. In patients with acute myocardial infarction, they correlate with 1-year prognosis. ET receptor antagonists have been widely studied in experimental models of cardiovascular disease. In arterial hypertension, they prevent vascular and myocardial hypertrophy. Experimentally, ET receptor blockade also prevents endothelial dysfunction and structural vascular changes in atherosclerosis due to hypercholesterolemia. In experimental myocardial ischemia, treatment with an ET receptor antagonist reduced infarct size and prevented left ventricular remodeling after myocardial infarction. Most impressively, treatment with the selective ET(A) receptor antagonist BQ123 significantly improved survival in an experimental model of heart failure. In many clinical conditions, such as congestive heart failure, both mixed ET(A/B )as well as selective ET(A) receptor antagonism ameliorates the clinical status of patients, i.e. symptoms and hemodynamics. A randomized clinical trial showed that a mixed ET(A/B) receptor antagonist effectively lowered arterial blood pressure in patients with arterial hypertension. In patients with primary pulmonary hypertension or pulmonary hypertension related to scleroderma, treatment with a mixed ET(A/B) receptor antagonist resulted in an improvement in exercise capacity. ET receptor blockers thus hold the potential to improve the outcome in patients with various cardiovascular disorders. Randomize

Topics: Animals; Arteriosclerosis; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Hypertension, Pulmonary; Myocardial Infarction; Renal Insufficiency

Initial pharmacologic therapy for hypertension is low-dose thiazide diuretics, beta-blockers, and ACE inhibitors. Increasing data have confirmed that ACE inhibitors have specific benefit in patients with diabetes, atherosclerosis, left ventricular dysfunction, and renal insufficiency. CCBs are alternative agents for ISH in the elderly and appear to decrease stroke with perhaps less protection against progression of renal insufficiency and proteinuria, CAD mortality and new onset heart failure versus other initial agents, especially ACE inhibitors. ARBs are well tolerated and effective blood pressure lowering agents but have not been confirmed as effective as ACE inhibitors for reducing renal progression, clinical events, or mortality from heart failure. Effective pharmacologic antihypertensive therapy may avoid disabling and undetected cerebrovascular disease, cognitive dysfunction, and disturbing symptoms of elevated blood pressure. Vasopeptidase inhibitor, such as omapatrilat, and endothelin-1 antagonist, such as bosentan, may become future agents approved for the reduction of morbidity and mortality with hypertension. The ALLHAT trial continues to examine the potential benefits and harms of amlodipine versus chlorthalidone and lisinopril in a diverse high-risk population. Based on ALLHAT data, however, doxazosin is no longer an acceptable initial pharmacological agent. Intensive pharmacologic treatment with blood pressure lowering to less than 130/85 mm Hg is recommended with diabetes, renal insufficiency, and heart failure with additional goal of less than 125/75 mm Hg with renal failure and proteinuria greater than 1 g/24 h, based on multiple outcome studies.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteriosclerosis; Bosentan; Bradykinin; Calcium Channel Blockers; Diabetes Complications; Diuretics; Drug Therapy, Combination; Endothelin-1; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Patient Compliance; Pyridines; Quality of Life; Renal Insufficiency; Renin-Angiotensin System; Risk Factors; Sulfonamides; Systole; Thiazepines; Treatment Outcome

The degree to which ET-1 participates in the pathogenesis of renal dysfunction remains poorly understood. In the kidney, ET-1 not only produces vasoconstriction, but also vasodilation in the renal medulla, stimulation of sodium reabsorption in the proximal tubule, and inhibition of reabsorption in a variety of nephron segments. It is clear that ET-1 production is increased in most forms of renal failure, although the cause of this increase is not known. Endothelin receptor antagonists, as therapeutic agents, have been investigated in a large variety of animal models, and even though there have been some promising results, there are many conflicting reports. While there is little known about the therapeutic utility of endothelin receptor antagonists in human renal failure, progress is most likely to be slow due to the complex nature of ET-1 actions and the less than promising initial studies in humans.

Topics: Animals; Endothelin-1; Humans; Kidney; Renal Insufficiency; Vasoconstriction

The aging process determines several modifications of the kidney, that, however, do not provoke any dysfunction in normal conditions. But in the elderly--in the presence of stressful situations and particularly when adrenergic activation is present--the kidney is more vulnerable than in the young, and renal failure may arise. Variations typical of the aging kidney are accelerated when hypertension overlaps the physiological renal process, because both senescence and hypertension weight on the same structures, i.e. glomeruli. We studied renal hemodynamic adaptation capacity both in the healthy elderly and in patients affected by isolated systolic hypertension, in an acute experiment which requires the application of a mental stress-induced adrenergic activation. In hypertensive patients we have already demonstrated a total lack of renal adaptation capacity. In fact, while the elderly normotensives react with a prolonged and pronounced vasoconstriction, in those with isolated systolic hypertension, adrenergic activation induces a passive renal vasodilation and glomerular hyperfiltration. The anomalous adaptation capacity of renal hemodynamics is probably due to an impairment in the paracrine response of renal vasculature. Indeed in the hypertensive elderly, unlike in the normotensive one, no variations of autacoid production occur during the adrenergic activation. Following on from this, pattients affected by isolated systolic hypertension passively suffer the many hypertensive peaks which characterize their every day life. The altered renal autoregulation of the elderly with isolated systolic hypertension may explain the accelerated glomerulosclerosis and the greater incidence of renal damage and end-stage renal disease which characterize this condition. These aspects underline the primary role of the antihypertensive treatment of isolated systolic hypertension, not only for the prevention of cardiovascular mortality but also of renal damage and/or end-stage renal disease.

Topics: Aging; Animals; Autacoids; Cyclic GMP; Dinoprostone; Endothelin-1; Humans; Hypertension; Kidney; Renal Insufficiency; Stress, Physiological

Endothelin-1 (ET-1) was discovered 10 years ago. Because it is one of the most potent vasoconstrictors in vivo, a pathophysiological role for the peptide as a mediator of hypertension has been postulated. Several clinical studies, however, have been unable to identify elevated ET levels in the plasma of hypertensive patients, suggesting that it does not play a prominent role in this disease. More recently, evidence has been presented that ETs act predominantly at the autocrine/paracrine level and that measurements of plasma levels can give only an indirect view of the activity of the system. In addition, transgenic technology has uncovered new actions of the peptide systems in recent years, which point to a key function of the system in prenatal development. Moreover, investigation of conditions associated with hypertensive end-organ damage, such as chronic renal failure, has led to a re-evaluation of the role of the ET system in hypertension. This article discusses this recent evidence and defines the exact role of the ET system in hypertension and hypertensive end-organ damage.

Topics: Animals; Endothelin-1; Humans; Hypertension, Renal; Renal Insufficiency

Endothelial dysfunction is emerging as an important factor in the early development of acute and chronic renal disease. Drugs aimed specifically at rectifying this aberration are being developed, although other established agents such as calcium antagonists, angiotensin converting enzyme (ACE) inhibitors and HMG CoA reductase inhibitors also have beneficial effects in this setting. Calcium antagonists are particularly effective at ameliorating acute renal ischaemia associated with endothelial dysfunction. Combination therapy with a calcium antagonist and an ACE inhibitor might optimise the beneficial effects of calcium channel blockade on the sequelae of endothelial dysfunction in chronic renal failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Endothelin-1; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Nitric Oxide; Renal Insufficiency

Trichloroethylene (TCE) is a widely used industrial solvent that causes trichloroethylene hypersensitivity syndrome (THS) with multi-system damage, including kidney injury. Clinical studies have shown that the complement system is important for TCE-induced kidney injury. Our previous study found excessive deposition of complement C3, mainly on the glomerulus, indicating that local renal complement is activated after TCE sensitisation. However, whether local renal complement activation mediates TCE-induced immune kidney injury and the underlying mechanisms remain unknown. Therefore, we established a TCE percutaneous sensitisation BALB/c mouse model to explore the mechanisms by pretreating with or without the complement activation antagonist, cathepsin L inhibitor (CatLi). As expected, more C3 and C3a were detected mainly on glomerulus of TCE positive sensitisation (TCE

Topics: Animals; Complement Activation; Disease Models, Animal; Endothelin-1; Female; Hypersensitivity; Inflammation; Kidney; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; NF-kappa B; Renal Insufficiency; Signal Transduction; Trichloroethylene

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

To identify the risk factors of kidney injuries in hypertensive patients with uric acid (UA) metabolic disorders in order to choose the optimal management tactics, by analyzing the changes in markers for endothelial dysfunction (endothelin-1 (ET-1), microalbuminuria (MAU), intima-media thickness (IMT)) and tubulointerstitial tissue lesion (beta2-microglobulin (beta2-MG, monocyte chemotactic protein-1 (MCP-1)).. Eighty-one patients with grade 1 hypertension without associated diseases, diabetes mellitus, or metabolic syndrome were examined. There were 3 study groups: 1) hyperuricosuria (n = 7); 2) hyperuricemia (n = 53); 3) hyperuricemia and renal failure (n = 6); and a control group of 15 hypertensive patients without UA metabolic disorders who were matched for age and gender with the patients of the study groups.. The hypertensive patients with hyperuricemia, as compared with those without UA metabolic disorders, showed higher plasma concentrations of ET-1 (p = 0.003) and MAU (p = 0.009) and more marked increases in common carotid IMT (p = 0.044), urinary excretion of beta2-MG (p = 0.010), and MCP-1 (p = 0.030). There were direct correlations between all the examined biomarkers and the degree of uricemia (Rs = 0.453; p < 0.001; Rs = 0.411; p < 0.001; Rs = 0.322; p = 0.067; Rs = 0.537; p < 0.001; and Rs = 0.318; p = 0.004, respectively) and between the markers of endothelial dysfunction and those of tubulointerstitial tissue lesion (Rs = 0.295 for ET-1 and MCP-1; p = 0.008; Rs = 0.399 for ET-1 and beta2-MG; p < 0.001; Rs = 0.462 for MAU and beta2-MG; p < 0.001; and Rs = 0.188 for MAU and MCP-1; p = 0.094). Multivariate analysis of the clinical and laboratory parameters under study confirmed the role of serum MCP-1, beta2-MG, MAU, creatinine levels as independent predictors for decreased relative urinary gravity, the clinical sign of tubulointerstitial tissue lesion/fibrosis, and that of a wider range of the indicators, such as MAU, ventricular septal thickness, glomerular filtration rate, relative urinary gravity, systolic blood pressure, MPC-1, low-density lipoproteins, as risk factors for renal filtrating dysfunction.

Topics: Albuminuria; beta 2-Microglobulin; Biomarkers; Chemokine CCL2; Comorbidity; Endothelin-1; Endothelium; Female; Humans; Hypertension; Hyperuricemia; Male; Metabolic Diseases; Middle Aged; Nephritis, Interstitial; Renal Insufficiency; Risk Factors; Uric Acid

Impaired nitric oxide (NO) release in chronic renal failure has been implicated in the pathogenesis of hypertension and the progression of renal insufficiency. We investigated whether gene delivery of the endothelial NO synthase (eNOS) improves NO release and reduces blood pressure and renal failure and injury in rats with reduced renal mass.. Renal failure was induced by renal artery branches ligation. Two weeks later, rats with renal failure were divided into three groups and received an intravenous injection of the vehicle or the adenovirus that expresses eNOS or β-galactosidase (β-gal). Systolic blood pressure, renal parameters and histopathology were assessed at Week 4 after gene delivery.. At the end of the study, systolic blood pressures, serum creatinine, proteinuria, urinary endothelin-1 (ET-1) excretion and renal cortex ET-1 levels were increased, whereas plasma and urine NO(2)/NO(3) were reduced in renal failure rats as compared to normal controls. Renal injury comprised blood vessel media hypertrophy, focal and segmental glomerular sclerosis, tubular atrophy and interstitial fibrosis. Gene delivery of eNOS, but not β-gal, prevented an increase in systolic blood pressure and proteinuria, and a reduction in plasma and urine NO(2)/NO(3). eNOS gene delivery also reduced a rise in serum creatinine, urinary ET-1 excretion and renal cortex ET-1 levels, and the renal vascular, glomerular and tubular injury.. This study indicates that eNOS gene delivery in rats with renal failure improves NO release, which likely prevents the aggravation of hypertension and slows down the progression of renal failure and injury.

Topics: Acute Kidney Injury; Adenoviridae; Animals; beta-Galactosidase; Cattle; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Hypertension; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Renal Insufficiency

Rats with 5/6 nephrectomy have metabolic acidosis with a progressive decline in the glomerular filtration rate (GFR) ameliorated by endothelin and aldosterone antagonists and by dietary alkali. Interestingly, rats with 2/3 nephrectomy have no metabolic acidosis yet have a progressive GFR decline induced by acid retention and ameliorated by dietary alkali. Because patients without metabolic acidosis but with a moderately reduced GFR have a progressive GFR decline, ameliorated by oral sodium bicarbonate, we used rats with 2/3 nephrectomy to model these patients. Kidney acid content, endothelin-1, and aldosterone (measured by microdialysis) were higher in the rats with 2/3 nephrectomy than those with a sham operation despite no differences in plasma acid-base parameters. The GFR of the former but not the latter was lower at 25 than at 1 week after nephrectomy. Endothelin and aldosterone antagonism improved the preservation of GFR; however, this remained lower at week 24 than at week 1. By contrast, the GFR at weeks 24 and 1 was not different if the rats were given dietary alkali to normalize the kidney acid content. Antagonist of endothelin and aldosterone yielded no added GFR benefit. Thus, our study shows that (1) the decline in GFR in 2/3 nephrectomy is mediated by acid retention-induced kidney endothelin and aldosterone production; (2) receptor antagonism and dietary alkali are not additive; and (3) dietary alkali better preserves GFR than both endothelin and aldosterone receptor antagonism.

Topics: Acid-Base Equilibrium; Acidosis; Administration, Oral; Aldosterone; Animals; Bicarbonates; Calcium Gluconate; Dietary Supplements; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Eplerenone; Female; Glomerular Filtration Rate; Kidney; Male; Microdialysis; Mineralocorticoid Receptor Antagonists; Nephrectomy; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; Renal Insufficiency; Spironolactone; Time Factors

In this article, the authors discuss three pathophysiologic mechanisms that influence the coagulation system in patients who have liver disease. First, bacterial infections may play an important role in the cause of variceal bleeding in patients who have liver cirrhosis, affecting coagulation through multiple pathways. One of the pathways through which this occurs is dependent on endogenous heparinoids, on which the authors focus in this article. Secondly, the authors discuss renal failure, a condition that is frequently encountered in patients who have liver cirrhosis. Finally, they review dysfunction of the endothelial system. The role of markers of endothelial function in cirrhotic patients, such as von Willebrand factor and endothelin-1, is discussed.

Topics: Bacterial Infections; Biomarkers; Blood Coagulation; Blood Coagulation Disorders; Endothelin-1; Endothelium, Vascular; Heparinoids; Humans; Liver Cirrhosis; Renal Insufficiency; Varicose Veins; von Willebrand Factor

We investigated the role of angiotensin II and endothelin-1 using the angiotensin AT1 receptor antagonist losartan and the endothelin ETA receptor antagonist atrasentan, in malignant hypertension and renal failure and damage induced by nitric oxide (NO) synthase inhibition in Harlan Sprague-Dawley (SD) rats. We also evaluated whether the protective effects of losartan go beyond the blood pressure reduction. Within only 3 weeks of treatment with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), Harlan SD rats developed malignant hypertension with renal failure and injuries. The latter were comprised of fibrinoid necrosis of small arteries and glomerular and tubular necrosis. Although both losartan and atrasentan attenuated the development of hypertension and renal failure, losartan only prevented the renal damage. In contrast to antrasentan, the vasodilator hydralazine reduced blood pressure and prevented the renal injuries similar to losartan. However, when these treatments were prolonged to 5 weeks, losartan, but not hydralazine, was still effective in reducing renal failure and damage, despite a marked increase in blood pressure. Our results indicate that angiotensin II and endothelin-1 play a differential role in the pathogenesis of malignant hypertension and in vascular and renal damage induced by L-NAME in Harlan SD rats. Although the protective effects of atrasentan may depend on the reduction of blood pressure, which was shown to retard the development of renal injury using hydralazine, those of losartan go beyond the blood pressure reduction. Hence, tissue protective effects of angiotensin AT1 receptor blockade may be pivotal for long-term vascular and renal protection.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Atrasentan; Blood Pressure; Endothelin-1; Hydralazine; Hypertension, Malignant; Losartan; Male; Necrosis; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renal Insufficiency

Topics: Animals; Antihypertensive Agents; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Humans; Hypertension, Pulmonary; Renal Insufficiency

The risk of cardiovascular disease in uremic patients is greater in male than in female patients. Estrogens seem to play a cardioprotective role until menopause. Experimental data on the effect of estrogens on cardiovascular damage are controversial and potential underlying mechanisms especially in renal failure have not been fully clarified.. Three-month-old female uninephrectomized stroke-prone spontaneously hypertensive (SHRsp) rats were sham-operated or ovariectomized. Subsequently, they received either vehicle (sesame oil) or 17-beta-3 benzoate estradiol (E2) (25 microg/day) or estriol (E3) (0.02 mg/day), respectively. After 3 months the animals were sacrified and the organs were harvested using pressure-controlled perfusion fixation. Stereologic parameters such as capillary length density (L(V)), mean intercapillary distance (MID), and volume density of the interstitial tissue (Vv) were quantitated. Additionally, expression of transforming growth factor-beta (TGF-beta), vascular endothelial growth factor (VEGF), flt-1, endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), endothelin A receptor (ETA) receptor, and alpha estrogen receptor was assessed using immunohistochemistry. Intramyocardial capillaries and the aorta were investigated by morphometric methods.. L(V) (mm/mm(3)) was significantly lower (2421 +/- 500) and MID (microm) significantly higher (22.2 +/- 2.33) in vehicle-treated uninephrectomized/ovariectomized compared to uninephrectomized/sham-ovariectomized controls (L(V) 3629 +/- 960, MID 12.7 +/- 2.7) as well as estradiol (L(V) 3340 +/- 739, MID 12.1 +/- 4.96) and estriol (L(V) 4655 +/- 618, MID 14.2 +/- 2.89) treated uninephrectomized/ovariectomized animals. The volume density of the cardiac interstitium was higher in vehicle-treated uninephrectomized/ovariectomized animals compared to uninephrectomized/sham-ovariectomized, estradiol and estriol treated uninephrectomized/ovariectomized rats. The protein level expression of TGF-beta was higher in vehicle treated uninephrectomized/ovariectomized compared to uninephrectomized/sham and all treatment groups.. In ovariectomized SHRsp rats with moderate renal failure cardiac lesions were strikingly less after estradiol or estriol treatment. The results document a beneficial role of estrogens on cardiac abnormalities in a model of moderate renal dysfunction.

Topics: Animals; Aorta; Arterioles; Endothelin-1; Estrogens; Female; Heart; Immunohistochemistry; Myocardium; Nephrectomy; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Ovariectomy; Rats; Rats, Inbred SHR; Renal Insufficiency; RNA, Messenger; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

To elucidate the role of nitric oxide (NO) in the pathogenesis of ischemic acute renal failure, we examined the effects of (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409) and N(G)-nitro-L-arginine methyl ester (L-NAME) as a NO donor and a non-selective NO synthase inhibitor on ischemia/reperfusion-induced renal injury and renal endothelin-1 content. Ischemic acute renal failure was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. At 24 h after reperfusion, renal function in untreated acute renal failure rats markedly decreased and histological examination revealed severe renal damage. In addition, increases in renal endothelin-1 contents were evident in the acute renal failure rats at 2, 6, and 24 h after reperfusion, respectively. Pretreatment with FK409 (1 or 3 mg/kg, i.v.) attenuated ischemia/reperfusion-induced renal dysfunction, histological damage, and endothelin-1 overproduction after reperfusion. In contrast, pretreatment with L-NAME (1 or 10 mg/kg, i.v.) aggravated renal injuries of acute renal failure rats at 24 h after reperfusion, and the effect is accompanied by further increases in the renal endothelin-1 content at 2 and 6 h, but not at 24 h, after reperfusion. These results suggest that suppressive effects of NO on the renal endothelin-1 overproduction induced by ischemia/reperfusion in an early phase are probably responsible for the protective effect of NO against ischemic acute renal failure.

Topics: Animals; Dose-Response Relationship, Drug; Endothelin-1; Kidney; Kidney Function Tests; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitro Compounds; Protective Agents; Rats; Rats, Sprague-Dawley; Renal Insufficiency; Reperfusion Injury; Time Factors

This study was designed to investigate the role of eicosanoids, thromboxane A2 (TXA2) and prostacyclin (PGI2) as well as their relationship with endothelin-1 (ET-1) in the pathogenesis of renal parenchymal hypertension. Uremic rats were prepared by renal mass ablation and compared with sham-operated controls. The stable metabolites of TXA2 (TXB2) and PGI2 (6-keto-PGF1alpha) and immunoreactive ET-1 concentrations were measured by specific RIAs in biological fluids and in vascular and renal tissues. To investigate the functional role of TXA2 in the progression of hypertension and renal failure, a group of uremic rats were treated with ridogrel (25 mg/kg/day), a TXA2 synthase inhibitor and receptor antagonist. Renal preproET-1 expression was assessed by Northern blot analysis. Systolic blood pressure (SBP), serum creatinine and proteinuria were found to be higher in uremic rats as compared to sham-operated controls (P < 0.01). TXB2 and ET-1 concentrations were increased in blood vessels, the renal cortex and in urine (P < 0.05). 6-keto-PGF1alpha concentrations were also increased in blood vessels and the renal cortex but decreased in urine (P < 0.05). Ridogrel significantly lowered SBP and proteinuria (P < 0.05) and blunted the increase of serum creatinine. Treatment with ridogrel resulted in a marked fall in vascular, renal and urine TXA2 concentrations, while ET-1 and 6-keto-PGF1alpha concentrations remained unchanged. The preproET-1 expression was higher in uremic rats than in the controls and was unaffected by ridogrel. These results suggest that TXA2 is involved in the pathogenesis of hypertension and renal failure progression in rats with subtotal 5/6 nephrectomy and that this effect is independent of the ET-1 system.

Topics: Animals; Blood Pressure; Disease Models, Animal; Disease Progression; Eicosanoids; Endothelin-1; Epoprostenol; Male; Rats; Rats, Wistar; Renal Insufficiency; Thromboxane A2; Time Factors; Uremia

Laparoscopic pneumoperitoneum has been shown to decrease glomerular filtration rate (GFR) and urine volume (UV). Endothelin-1 (ET-1), a potent renal vasoconstrictor, has been implicated. The purpose of this study was to determine renal function, ET-1 gene expression, and peptide localization in kidneys subjected to CO2 pneumoperitoneum.. Experiments were performed in three groups of anesthetized Sprague-Dawley rats in which GFR and UV were measured before, during, and after insufflation. In the first group (n = 8), pneumoperitoneum (10 mmHg) was established for 30 min. The second group (n = 4) underwent a sham operation without pneumoperitoneum. In the final group (n = 4), kidneys were obtained from normal control animals without any prior surgical instrumentation. PreproET-1 (ppET-1) mRNA levels were measured by reverse transcription-polymerase chain reaction (RT-PCR). The ET-1 peptide was localized within kidneys by immunohistochemistry (IHC).. Pneumoperitoneum caused a significant (p < 0.05) 87% decrease in GFR and a 79% decrease in UV from baseline, with a return to baseline values after desufflation. RT-PCR showed a significant (p < 0.05) increase in expression of ppET-1 mRNA in the laparoscopic group; it was 3.52 +/- 0.33 densitometric units (DU), as compared to 0.35 +/- 0.06 DU and 0.57 +/- 0.12 DU in the control and sham groups, respectively. IHC showed enhanced expression of the ET-1 peptide in the vascular endothelium and proximal tubular cells of the laparoscopic group compared to the control and sham groups.. Pneumoperitoneum induces ET-1 gene and peptide upregulation in the kidney. Expression of ET-1 is increased in the renal vasculature and proximal tubular cells. The elevation of ET-1 and its localization may account for some of the renal dysfunction observed during pneumoperitoneum. This suggests that antagonism of ET-1 may be beneficial in patients with renal impairment undergoing prolonged laparoscopic procedures or in protecting allograft function during and after living donor nephrectomy.

Topics: Animals; Base Sequence; Endothelin-1; Kidney Function Tests; Laparoscopy; Male; Models, Animal; Molecular Sequence Data; Pneumoperitoneum, Artificial; Probability; Rats; Rats, Sprague-Dawley; Reference Values; Renal Insufficiency; Reverse Transcriptase Polymerase Chain Reaction; Risk Assessment; RNA, Messenger; Up-Regulation

Remodeling of vessels is a known feature of renal failure, but it is unclear whether this represents an appropriate or inappropriate response to the known changes in blood flow, shear stress, and wall tension. To investigate remodeling in response to variations in blood flow, first-order mesenteric arteries were exposed to high- and low-flow conditions via the ligation of second-order branches, according to the technique described by Pourageaud and De Mey. The resulting changes in vessel geometric features, relative proportions of intima and media, submicroscopic structure, and immunostaining for proliferating cell nuclear antigen (PCNA), endothelin-1 (ET-1), and ET(A) receptors were assessed in first-order mesenteric arteries under low-flow and high-flow conditions. Subtotally nephrectomized (SNX) animals were compared with sham-operated rats. Animals either were left untreated or were treated with the ET(A) receptor antagonist (ET-RA) LU-135252, because of suggestions in the literature that ET is involved in vascular remodeling in uremia. A highly significant increase in intimal thickness was noted in low-flow arteries (4.21 +/- 1.39 microm) of SNX animals, compared with normal-flow arteries (2.06 +/- 0.61 microm), but this increase was not observed in sham-operated rats (1.38 +/- 0.77 in low-flow arteries versus 2.40 +/- 0.35 microm in normal-flow arteries). The increase in intimal thickness in low-flow arteries was abrogated by ET-RA. The medial thickness was increased in untreated SNX animals (19.5 +/- 3.61 microm), compared with sham-operated rats, and this increase was also prevented by ET-RA. The medial thickness was not affected by low flow in either sham-operated or SNX animals. In parallel, the number of PCNA-positive intimal cells was higher in low-flow, but not high-flow, arteries of SNX rats, compared with sham-operated rats. No significant change was observed in sham-operated animals. In the media, the number of PCNA-positive cells was higher in untreated SNX animals than in sham-operated rats. The number was even more markedly increased in high-flow, but not low-flow, vessels. This increase was abrogated by ET-RA. It is concluded that, in uremic animals, the response of the intima to low flow and the response of the media to high flow are exaggerated. Both responses are apparently mediated by ET.

Topics: Animals; Aorta; Cell Division; Endothelin Receptor Antagonists; Endothelin-1; Immunohistochemistry; Male; Mesenteric Arteries; Microscopy, Electron; Nephrectomy; Phenylpropionates; Proliferating Cell Nuclear Antigen; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin; Renal Insufficiency; Tunica Intima; Tunica Media; Vascular Resistance

The renin-angiotensin system (RAS) and endothelin system may both play a role in the pathogenesis of progressive renal injury. The aims of the present study were 3-fold: first, to explore the possible benefits of dual blockade of the RAS with an ACE inhibitor and an angiotensin type 1(AT1) receptor antagonist; second, to examine the relative efficacy of endothelin A receptor antagonism (ETA-RA) compared with combined endothelin A/B receptor antagonism (ETA/B-RA); and third, to assess whether interruption of both RAS and endothelin system had any advantages over single-system blockade. Subtotally nephrectomized rats were studied as a model of progressive renal injury and randomly assigned to one of the following treatments for 12 weeks: perindopril (ACE inhibitor), irbesartan (AT1 receptor antagonist), BMS193884 (ETA-RA), bosentan (ETA/B-RA), and a combination of irbesartan with either perindopril or BMS193884. Treatment with irbesartan or perindopril was associated with an improved glomerular filtration rate and reductions in blood pressure, urinary protein excretion, glomerulosclerosis, and tubular injury in association with reduced gene expression of transforming growth factor-beta(1) and matrix protein type IV collagen. The combination of irbesartan with perindopril was associated with further reductions in blood pressure and urinary protein excretion. No beneficial effects of either BMS193884 or bosentan were noted. Furthermore, the addition of BMS193884 to irbesartan did not confer any additional benefits. These findings suggest that the RAS but not the endothelin system is a major mediator of progressive renal injury after renal mass reduction and that the combination of an AT1 receptor antagonist with an ACE inhibitor may have advantages over the single agent of RAS blocker treatment.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Collagen; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelin-1; Glomerular Filtration Rate; Kidney; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Endothelin A; Receptor, Endothelin B; Renal Insufficiency; Renin-Angiotensin System; RNA, Messenger; Severity of Illness Index; Transforming Growth Factor beta

Fluid retention is a major characteristic of symptomatic, progressive heart failure when a main factor implicated in the pathogenesis of renal dysfunction is renal hypoperfusion. This may be a consequence of forward cardiac failure, resulting in a low cardiac output integrating poor left ventricular function secondary to myocardial impairment and increased resistance in the regional renal vasculature secondary to locally released vasoconstrictors, e.g. endothelin. So far, the role of the pulmonary circulation in perpetuating renal dysfunction in heart failure is unclear.. We investigated the relationship of hemodynamic variables obtained during right heart catheterization and plasma big endothelin levels to renal function variables in 18 male patients aged 52 +/- 3 years, with heart failure in the NYHA function class III-IV, based on idiopathic causes in 8 and ischemic causes in 10 patients. Renal plasma flow (RPF) was established by paraaminohippurate (PAH) clearance and the glomerular filtration rate (GFR) was measured by iothalamate clearance.. Plasma big endothelin (ET) levels were increased above the upper normal range (1.8 fmol/ml) in 16 out of 18 patients, averaging 5.0 +/- 0.8 fmol/ml (1.7-11.9 fmol/ml). Positive correlations to big ET plasma levels were detected with mean pulmonary pressure (r = 0.73, p < 0.001) pulmonary capillary wedge pressure (r = 0.56, p < 0.05) and pulmonary vascular resistance index (r = 0.69, p < 0.01). Glomerular filtration rate (70 +/- 7 ml/min) and renal plasma flow (358 +/- 36 ml/min) were considerably reduced and exhibited a tendency to correlate inversely with big ET levels (r = -0.46, p = 0.056 and r = -0.44, p = 0.069, respectively). Contrary to expectations, RPF did not correlate significantly with cardiac index, systemic vascular resistance index or arterial blood pressure. In contrast, significant correlations were detected of RPF with pulmonary capillary wedge pressure (r = -0.69, p < 0.01), mean pulmonary artery pressure (r = -0.65, p < 0.01), right atrial pressure (r = -0.47, p < 0.05) and right ventricular ejection fraction (r = 0.49, p < 0.05).. The findings suggest a role for endothelin in renal vasoconstriction and accord well with the concept that in severe heart failure renal hypoperfusion--by volume retention--as well as increased endothelin synthesis--by pulmonary vasoconstriction--play a part in the increased pulmonary filling pressures.

Topics: Endothelin-1; Endothelins; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Humans; Ischemia; Kidney; Male; Middle Aged; Protein Precursors; Pulmonary Circulation; Pulmonary Wedge Pressure; Renal Insufficiency; Vascular Resistance; Ventricular Function, Left; Ventricular Function, Right; Water-Electrolyte Balance

Plasma concentrations of big endothelin-1 were determined by ELISA in 18 patients with complicated Plasmodium falciparum malaria in Bangkok. Before therapy, elevated levels were recorded (21 +/- 12 vs. 2.9 +/- 1.1 pmol/L in age- and sex-matched healthy subjects; P < .001). Even 7 days after therapy, elevated concentrations were seen (25 +/- 14 pmol/L). Plasma endothelin levels were correlated with levels of tumor necrosis factor-alpha (r = .632, P < .01), and a negative correlation with platelet counts was seen (r = .783, P < .005). No relation between plasma endothelin concentrations and parasitemia, fever, or other indices of severe infection (hypotension, renal, hepatic or pulmonary impairment, cerebral malaria) existed. During and after complicated malaria, increased levels of plasma endothelin could contribute to malarial pathology or reflect endothelial damage or both.

Topics: Antimalarials; Artemisinins; Artesunate; Endothelin-1; Endothelins; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-6; Malaria, Cerebral; Malaria, Falciparum; Matched-Pair Analysis; Platelet Count; Protein Precursors; Renal Insufficiency; Sesquiterpenes; Tumor Necrosis Factor-alpha

In order to investigate endothelial cell dysfunction in patients with impaired renal function, we measured circulating endothelin (ET-1) and thrombomodulin (Tm) concentrations used as markers for endothelial cell injury in patients with renal failure. 1) ET-1 and Tm were significantly higher in patients with renal failure and pre-dialysis patients than in normal subjects. Tm in CRF patients was significantly greater than that in ARF patients. In contrast, ET-1 was significantly greater in ARF than in CRF. 2) A positive correlation was found between serum creatinine concentration (Cr) and Tm in pre-dialysis patients. However, no correlation was found between Cr and ET-1. 3) A positive correlation was found between Tm and the duration of dialysis in HD patients, but not in CAPD patients. 4) With the improvement of renal function after regular HD treatment, a substantial reduction was found in ARF patients in both Tm and ET-1, but not in CRF patients. The present study suggests the presence of endothelial cell dysfunction in patients with impaired renal function. The progression of endothelial cell damage may differ between patients on HD and those on CAPD. In addition, it is suggested that endothelial cell dysfunction reverses in ARF patients with improved renal function.

Topics: Acute Kidney Injury; Creatinine; Endothelin-1; Endothelium; Humans; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Renal Insufficiency; Thrombomodulin