endothelin-1 and Renal-Artery-Obstruction

Endothelin (ET)-1 is a potent vasoactive peptide which is mostly secreted toward the vessel wall and the circulatory levels of which are quite low; for these reasons changes in plasma ET-1 may be difficult to detect even after the application of strong stimuli, which, in theory, should profoundly alter its production. We have examined the effects of a number of such stimuli and found that in humans the only one which consistently increased plasma ET-1 was the exposure to hypobaric hypoxia; moreover under these circumstances the increments in plasma ET-1 were correlated with the changes in pulmonary systolic pressure, suggesting a role of circulating ET-1 in the adaptation of pulmonary vessels to high altitude. In contrast no consistent changes of ET-1 were observed in response to sympathetic activation induced either by exposure to cold, standing, reduction in blood pressure and blood withdrawal. In response to angioplasty of renal artery stenosis a concomitant reduction in plasma ET-1 and angiotensin II (AngII) was observed in patients who, prior to angioplasty, had a high degree of activation of the renin system, supporting the possibility that in these specific conditions AngII may actually stimulate ET-1 production in vivo.

Topics: Adaptation, Physiological; Angioplasty; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cold Temperature; Endothelin-1; Humans; Hypertension; Hypoxia; Kidney; Renal Artery Obstruction; Renin-Angiotensin System; Sympathetic Nervous System

We hypothesized that chronic specific endothelin-A (ET-A) receptor blockade therapy would reverse renal dysfunction and injury in advanced experimental renovascular disease. To test this, unilateral renovascular disease was induced in 19 pigs, and after 6 weeks, single-kidney hemodynamics and function was quantified in vivo using computed tomography. All pigs with renovascular disease were divided such that seven were untreated, seven were treated with ET-A blockers, and five were treated with ET-B blockers. Four weeks later, all pigs were restudied in vivo, and then killed and ex vivo studies performed on the stenotic kidney to quantify microvascular density, remodeling, renal oxidative stress, inflammation, and fibrosis. Renal blood flow, glomerular filtration rate, and redox status were significantly improved in the stenotic kidney after ET-A but not ET-B blockade. Furthermore, only ET-A blockade therapy reversed renal microvascular rarefaction and diminished remodeling, which was accompanied by a marked decreased in renal inflammatory and fibrogenic activity. Thus, ET-A but not ET-B blockade ameliorated renal injury in pigs with advanced renovascular disease by stimulating microvascular proliferation and decreasing the progression of microvascular remodeling, renal inflammation, and fibrosis in the stenotic kidney. These effects were functionally consequential as ET-A blockade improved single kidney microvascular endothelial function, renal blood flow, and glomerular filtration rate, and decreased albuminuria.

Topics: Animals; Biomarkers; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hypertension, Renovascular; Kidney; Microvessels; Multidetector Computed Tomography; Renal Artery Obstruction; Renal Circulation; Swine

Endarterectomy and bypass surgery to treat renal artery stenosis are increasingly shunned these days due to high risks of complications during and after the surgery. Striving to find a sound alternative solution, we pioneered the construction of a tissue engineered renovascular graft that could immediately restore the normal blood flow to kidneys and sustain renal functions without suffering restenosis after the surgery. A highly porous scaffold was first constructed by electrospinning polycaprolactone, poliglecaprone, gelatin and elastin, giving the vast majority of non-woven fibers in the scaffold a diameter below 1200 nm. To recapitulate the anatomical and functional signatures of renal arteries, a bi-layer vasculature comprising a smooth muscle layer topped by an endothelial layer was built on the scaffold. The vasculature witnessed a sustained proliferation for up to 10 days in vitro and robustly secreted prostacyclin and endothelin-1, evidencing that the vasculature was functionally comparable to native renal arteries. After 30 days as a renovascular graft in mice, the luminal diameter of the graft remained clear without a restenosis and an increased confluence of the endothelial layer was observed. The tensile test confirmed that the renovascular graft was mechanically superior to native renal arteries and retained this advantage within 30 days in vivo. Also, this renovascular graft sustained renal functions as evidenced by normal levels of serum creatinine, urine creatinine and serum urea nitrogen and the lack of edema in the kidney cortex. These results demonstrate that this renovascular graft holds a great therapeutic promise for renal artery stenosis.

Topics: Animals; Blood Vessel Prosthesis; Cells, Cultured; Creatinine; Dioxanes; Elastin; Endarterectomy; Endothelial Cells; Endothelin-1; Female; Gelatin; Mice; Mice, Inbred C57BL; Mice, SCID; Myocytes, Smooth Muscle; Polyesters; Polymers; Proteins; Renal Artery; Renal Artery Obstruction; Tissue Scaffolds

Endothelin (ET)-1, a potent renal vasoconstrictor with mitogenic properties, is upregulated by ischemia and has been shown to induce renal injury via the ET-A receptor. The potential role of ET-A blockade in chronic renovascular disease (RVD) has not, to our knowledge, been previously reported. We hypothesized that chronic ET-A receptor blockade would preserve renal hemodynamics and slow the progression of injury of the stenotic kidney in experimental RVD. Renal artery stenosis, a major cause of chronic RVD, was induced in 14 pigs and observed for 6 wk. In half of the pigs, chronic ET-A blockade was initiated (RVD+ET-A, 0.75 mg·kg(-1)·day(-1)) at the onset of RVD. Single-kidney renal blood flow, glomerular filtration rate, and perfusion were quantified in vivo after 6 wk using multidetector computer tomography. Renal microvascular density was quantified ex vivo using three-dimensional microcomputer tomography, and growth factors, inflammation, apoptosis, and fibrosis were determined in renal tissue. The degree of stenosis and increase in blood pressure were similar in RVD and RVD+ET-A pigs. Renal hemodynamics, function, and microvascular density were decreased in the stenotic kidney but preserved by ET-A blockade, accompanied by increased renal expression of vascular endothelial growth factor, hepatocyte growth factor, and downstream mediators such as phosphorilated-Akt, angiopoietins, and endothelial nitric oxide synthase. ET-A blockade also reduced renal apoptosis, inflammation, and glomerulosclerosis. This study shows that ET-A blockade slows the progression of renal injury in experimental RVD and preserves renal hemodynamics, function, and microvascular density in the stenotic kidney. These results support a role for ET-1/ET-A as a potential therapeutic target in chronic RVD.

Topics: Angiography; Animals; Apoptosis; Blood Pressure; Disease Progression; Endothelin A Receptor Antagonists; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Fibrosis; Hepatocyte Growth Factor; In Situ Nick-End Labeling; Inflammation; Kidney; Kidney Function Tests; Renal Artery Obstruction; Renal Circulation; Signal Transduction; Swine; Tomography; Vascular Endothelial Growth Factor A

To examine biomarkers of oxidative stress (oxs), and endothelin (ET)-1, in hypertensive patients with atherosclerotic renal artery stenosis (ARAS) and to evaluate the effect of percutaneous transluminal renal angioplasty (PTRA).. Baseline measurements were made immediately before renal angiography in patients with suspected ARAS (significant ARAS, n = 83, and non-RAS, n = 59) and in 20 healthy, matched controls. In patients with ARAS, analyses were repeated 4 weeks after PTRA. All patients were treated with statins and acetylsalicylic acid throughout.. At baseline there were no significant differences between groups in biomarkers of oxs, whereas high-sensitivity C-reactive protein and blood leukocytes were significantly elevated in group ARAS versus both healthy controls and group non-RAS. Plasma levels of ET-1 and uric acid were significantly increased in group ARAS versus healthy controls prior to angiography and were significantly reduced compared to baseline 4 weeks after PTRA. PTRA had no significant effects on biomarkers of oxs, inflammation or serum creatinine concentrations.. ARAS patients on treatment with antihypertensive agents, acetylsalicylic acid and statins showed elevated inflammatory indices but no increase in oxs. PTRA had no significant effects on inflammatory indices 4 weeks after intervention but reduced plasma ET-1 and uric acid.

Topics: Aged; Angioplasty; Atherosclerosis; Biomarkers; Endothelin-1; Female; Humans; Hypertension; Male; Middle Aged; Oxidative Stress; Renal Artery Obstruction; Uric Acid

To assess the value of renal vein renin , plasma endothelin (ET), nitric oxide (NO), calcitonin gene-related peptide (CGRP) in predicting the therapeutic effect of percutaneous renal artery stenting.. Selective renal angiography was performed in 60 patients with coronary artery disease and hypertension. All the patients with obvious unilateral renal artery stenosis (lumen narrowing >or =50%) underwent percutaneous transluminal renal angioplasty and stenting. Bilateral renal vein and inferior vena cava plasma renin activity (PRA) and plasma ET, NO, and CGRP levels were measured and the two-year follow-up data of the patients analyzed.. In all the patients, PRA in the ischemic kidney was significantly higher than that in the contralateral kidney (3.89-/+3.14 vs 2.01-/+1.93 nmol/L/h, P>0.05). After renal artery revascularization with stenting, PRA in the ischemic kidney was reduced obviously (P<0.05), which was significantly lower in patients with renal vein renin ratio (RVRR)>1.5 than in those with RVRR <1.5 (1.92-/+2.15 vs 2.42-/+0.56 nmol/L/h, P<0.05]. Plasma ET level was significantly higher, whereas plasma NO level significantly lower in patients with PVRR>1.5 (P<0.05). Greater improvement of blood pressure was observed in patients with RVRR>1.5 after two years than in those with RVRR< 1.5 (P<0.05).. The activity of penal vein renin, plasma ET, NO, and CGRP may provide valuable information for predicting the therapeutic effect of percutaneous renal artery stenting.

Topics: Aged; Angioplasty, Balloon; Calcitonin Gene-Related Peptide; Endothelin-1; Female; Humans; Hypertension, Renovascular; Male; Middle Aged; Nitric Oxide; Radiography; Renal Artery; Renal Artery Obstruction; Renal Veins; Renin; Stents

Coronary endothelial dysfunction is associated with an increase in cardiac events. Hypercholesterolemia (HC) and hypertension (HT) are both associated with endothelial dysfunction, and their coexistence is associated with an increased incidence of cardiac events in epidemiological studies. However, pathogenic mechanisms are poorly understood. Here we studied the effects of coexisting HC and HT on coronary endothelial function.. Four groups of pigs were studied after 12 weeks of a normal diet (n=9), a 2% HC diet (n=9), HT (achieved by unilateral renal artery stenosis, n=8), or HC+HT (n=6). Coronary endothelial function was tested, in epicardial arteries and arterioles, by using organ chamber techniques. Oxidative stress was measured in coronary artery tissue. Vasodilatory response to bradykinin and calcium ionophore was significantly impaired in animals with HC+HT compared with each risk factor alone (P<0.05 for both). In animals with coexistent HC and HT, the increase in oxidative stress was more pronounced compared with each risk factor alone (P<0.05). Furthermore, chronic antioxidant supplementation significantly improved coronary artery vasoreactivity.. These results suggest that HC and HT have a synergistic deleterious effect on coronary endothelial function, associated with increased oxidative stress. This interaction may contribute to the increased incidence of coronary heart disease and cardiac events seen when HC and HT coexist.

Topics: Animals; Antioxidants; Ascorbic Acid; Bradykinin; Calcimycin; Coronary Artery Disease; Coronary Vessels; Cyclic GMP; Diet, Atherogenic; Endothelin-1; Endothelium, Vascular; Female; Hemodynamics; Hypercholesterolemia; Hypertension, Renovascular; Lipids; Nitric Oxide; Nitroprusside; Oxidative Stress; Renal Artery Obstruction; Renin; Substance P; Swine; Vasodilator Agents; Vitamin E

Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of properties of HO and its products, we hypothesized that HO would be important for the regulation of blood pressure and ischemic injury. We studied chronic renovascular hypertension in mice deficient in the inducible isoform of HO (HO-1) using a one kidney-one clip (1K1C) model of disease. Systolic blood pressure was not different between wild-type (HO-1(+/+)), heterozygous (HO-1(+/-)), and homozygous null (HO-1(-/-)) mice at baseline. After 1K1C surgery, HO-1(+/+) mice developed hypertension (140+/-2 mm Hg) and cardiac hypertrophy (cardiac weight index of 5.0+/-0.2 mg/g) compared with sham-operated HO-1(+/+) mice (108+/-5 mm Hg and 4.1+/-0.1 mg/g, respectively). However, 1K1C produced more severe hypertension (164+/-2 mm Hg) and cardiac hypertrophy (6.9+/-0.6 mg/g) in HO-1(-/-) mice. HO-1(-/-) mice also experienced a high rate of death (56%) within 72 hours after 1K1C surgery compared with HO-1(+/+) (25%) and HO-1(+/-) (28%) mice. Assessment of renal function showed a significantly higher plasma creatinine in HO-1(-/-) mice compared with HO-1(+/-) mice. Histological analysis of kidneys from 1K1C HO-1(-/-) mice revealed extensive ischemic injury at the corticomedullary junction, whereas kidneys from sham HO-1(-/-) and 1K1C HO-1(+/-) mice appeared normal. Taken together, these data suggest that chronic deficiency of HO-1 does not alter basal blood pressure; however, in the 1K1C model an absence of HO-1 leads to more severe renovascular hypertension and cardiac hypertrophy. Moreover, renal artery clipping leads to an acute increase in ischemic damage and death in the absence of HO-1.

Topics: Acute Kidney Injury; Animals; Blood Pressure; Cardiomegaly; Chronic Disease; Creatinine; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Heterozygote; Homozygote; Hypertension, Renovascular; Immunohistochemistry; Kidney; Membrane Proteins; Mice; Mice, Knockout; Nephrectomy; Organ Size; Receptor, Endothelin A; Renal Artery Obstruction; RNA, Messenger; Severity of Illness Index; Survival Rate

Prognosis in Takayasu's arteritis is limited owing to renovascular hypertension. The authors report a patient with Takayasu's arteritis who had been unilaterally nephrectomized and presented with malignant hypertension due to renal artery stenosis. Hypertension was refractory to conventional antihypertensive treatment, and stenosis was not accessible by interventional angioplasty. Initiation of enalapril and losartan therapy was successful in improving blood pressure without deterioration of renal function due to ischemic failure. Antihypertensive treatment resulted in dramatically stimulated endogenous nitric oxide (NO) synthesis, while elevated plasma endothelin-1 levels were unchanged. Renovascular hypertension in Takayasu's arteritis is associated with an imbalance of vasoconstrictor peptide endothelin-1 and vasodilator peptide NO. Successful treatment of hypertension by enalapril or losartan results in improved endogenous NO synthesis, which putatively counterbalances excessive vasoconstrictor actions and may retard the progression of renal failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Enalapril; Endothelin-1; Female; Humans; Hypertension, Renovascular; Losartan; Middle Aged; Nephrectomy; Nitric Oxide; Prognosis; Renal Artery Obstruction; Takayasu Arteritis; Vasoconstrictor Agents; Vasodilator Agents