Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To find out which of the effects of angiotensin converting enzyme (ACE) inhibitors on the fetus are due to their actions in the mother and which are direct effects due to blockade of the fetal renin-angiotensin system, enalapril (150 mg twice daily i.v.), which does not readily cross the sheep placenta, was given for 3 days to nine chronically catheterized pregnant ewes, 5 days after fetal urine and lung liquid had been continuously drained and while drainage of these fetal fluids continued. Drainage of fetal fluids was carried out so that a net sodium deficit would be incurred, and the dependency of the ewe on the activity of her renin-angiotensin system (RAS) for maintenance of her arterial pressure and fluid and electrolyte balance would be increased. During drainage of fetal fluids ewes drank more and increased their net water balance (p < 0.025). With enalapril, ewes became hypotensive (p < 0.005), but heart rate did not change. Maternal plasma potassium (K) levels increased (p < 0.05) and the plasma sodium to potassium ratio (Na:K) decreased (p < 0.005). Enalapril did not reduce maternal water intake nor change her urine output. After 5 days of drainage, fetal plasma K levels (p < 0.05) were higher and plasma Na:K (p < 0.025) was lower. After maternal enalapril, lung liquid flow and electrolyte excretion were transiently reduced (p < 0.05). Fetal plasma K levels increased further (p < 0.025) and plasma Na:K ratio decreased (p < 0.025 - p < 0.01). Fetal arterial PO2 was reduced 2 h after enalapril (p < 0.005) and was low on the last 2 days of treatment. Although fetal fractional reabsorption of K fell (p < 0.01) by the last day of enalapril treatment, the increase in fetal K excretion was not significant, because by this time sufficient enalapril was present in the fetal circulation to reduce glomerular filtration rate (GFR, p < 0.025 - p < 0.001). It is concluded that the toxicity of ACE inhibitors may be related to those effects in the ewe that lead to reduced fetal arterial oxygen levels and increased fetal plasma K levels. In the latter case it is postulated that inhibition of the maternal RAS may leave ewe and fetus deficient in aldosterone, leading to the rise in K levels. Thus the toxic effects of ACE inhibitors can be mediated through their effects on the mother, but their ability to cause fetal renal failure and oligohydramnios is due to their direct effects on the fetal RAS.
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PMID:Effects of inhibition of the maternal renin-angiotensin system on maternal and fetal responses to drainage of fetal fluids. 896 Mar 88

The renin-angiotensin system is associated with a variety of pathophysiological processes in many organ systems, and is known to be involved in the normal regulation of blood pressure and in the pathogenesis of renovascular hypertension. Angiotensin II is a multifunctional hormone that manifests its properties by interacting with two major subtypes of cell surface receptors (AT1 and AT2). Angiotensin converting enzyme (ACE) inhibitors are able to modify the actions of the renin-angiotensin system, and are indicated for the treatment of hypertension and heart disease. The antihypertensive effects of ACE inhibiting drugs are related to their ability to block the conversion of the decapeptide, angiotensin I, to the potent pressor octapeptide, angiotensin II. ACE inhibitors have been implicated in fetopathies in humans and perinatal mortality in rats, rabbits, sheep and baboons. Human fetopathies were seen when ACE inhibitors were given around the 26th week of gestation. The major adverse effects in babies include: oligohydramnios, renal tubular dysgenesis, neonatal anuria, calvarial and pulmonary hypoplasia, mild to severe intrauterine growth retardation, persistent patent ductus arteriosus and fetal or neonatal death. These developmental anomalies are thought to be partly due to a direct action of ACE inhibitors on the fetal renin-angiotensin system and partly due to the ischemia resulting from maternal hypotension and decreases in fetal-placental blood flow and oxygen/nutrient delivery to the fetus. The purpose of this review is to briefly discuss the pathophysiological role of the renin-angiotensin system, the therapeutic uses of ACE inhibitors in pregnant patients and to focus primarily on the major fetotoxic effects of ACE inhibitors encountered in humans and animal models. I will also review our recent data which show that capozide (captopril + hydrochlorothiazide) not only produces oligohydramnios but also disturbs the balance of glucose and NaCl in the maternal plasma and amniotic fluid of the rat.
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PMID:An overview of the influence of ACE inhibitors on fetal-placental circulation and perinatal development. 940 46

Twin-twin transfusion syndrome (TTTS) complicates one in five monochorionic pregnancies and is generally associated with high mortality and morbidity. One twin (the recipient) grows appropriately and has polyhydramnios while the other (the donor) may have a reduced growth velocity and severe oligohydramnios. The disparities in amniotic fluid volumes represent differences in fetal urine output. These differences occur secondary to hemodynamic changes, in which the vascular arrangement of placental anastomoses in TTTS leads to unidirectional flow from the donor to the recipient twin. A better understanding of the pathophysiology may contribute to improved management of this morbid condition. We studied three consecutive prospectively diagnosed stillborn twin pairs affected by early-onset TTTS. Renin gene expression was studied in sections of fetal kidneys with immunocytochemistry using a renin antiserum and with in situ hybridization using riboprobes complementary to renin mRNA, and renin-secreting cells (RCC) were counted. The overall maturation of the renal cortex was assessed by the percentage of immature glomeruli. The donor twin kidneys were smaller than those of the recipients, but the maturation of the renal cortex was not significantly different (28.2% immature glomeruli in the donor and 24.4% in the recipient kidney). The donor kidney showed increased renin gene expression with hyperplastic juxtaglomerular apparatuses (JGAs) that contained excess RCCs (median 20.02 [25th-75th centiles, 5.4, 25.1 RCCs per 100 glomeruli]). In contrast, the recipient kidney was virtually devoid of these cells (0.04 [0, 0.36] RCCs per 100 glomeruli; P < 0.05). In the donor kidney, increased renin release may, by a local action, contribute to renal vasoconstriction and oliguria. Increased renin and/or angiotensin II in the blood passing through the placental anastomoses may, by an endocrine action, suppress renin synthesis in the recipient kidney, thereby increasing renal blood flow and causing polyuria and polyhydramnios. These changes in the renal RAS could thus contribute to the pathogenesis of TTTS. The renal renin changes noted here may represent a contributory or compensating mechanism, the success of which may dictate the overall survival of the twin pregnancy and allow better understanding of the pathophysiology and perhaps therapy that may be employed in this condition.
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PMID:Renin gene expression in fetal kidneys of pregnancies complicated by twin-twin transfusion syndrome. 1117 34

In spite of active perinatal management, twin-twin transfusion syndrome (TTTS) remains a severe disease with a high risk of neonatal mortality and morbidity. TTTS initially results from an unbalanced blood flow from a donor to a recipient twin. However, its pathogenesis remains unclear, although cardiovascular disturbances and regulation of fetal volemia and diuresis seem central in this syndrome. Previously, we demonstrated that the renin-angiotensin system (RAS) was up-regulated in donor twins as a consequence of hypovolemia, and down-regulated in recipients. This was the first evidence of the implication of the RAS in TTTS. We hypothesize that the RAS plays a key role in the pathogenesis of TTTS. In the donor, RAS up-regulation aggravates oligohydramnios and may increase arterial resistance, which could contribute to placental dysfunction leading to intrauterine growth restriction. In the recipient, paradoxical RAS activation, due to transfer of effectors such as angiotensin II through placental shunts, could explain fetal vascular disturbances and cardiomyopathy. According to our hypothesis, TTTS would appear similar to the classical model of hypertension referred to as '2 kidneys-1 clip' with a donor twin, comparable to the clipped kidney, intoxicating its cotwin, comparable to the normal kidney.
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PMID:Pathogenesis of twin-twin transfusion syndrome: the renin-angiotensin system hypothesis. 1139 88

Non-steroidal anti-inflammatory drugs (NSAID) are used since years as tocolytic due to their capacity to inhibit cyclo-oxygenase (COX) expressed in uterus and fetal membranes, fundamental for labour initiation and maintenance. The use of nimesulide, a COX-2 selective NSAID, has been recently proposed due to its capacity to selectively inhibit the enzyme expressed in the myometrium and endometrium. A case of neonatal irreversible end stage renal failure after maternal assumption of nimesulide as tocolytic for 6 week is reported. Cesarean section at the 32nd week due to oligohydramnios gave birth to a baby girl of 2090 g, in good general conditions, without signs of respiratory distress and of visible abnormalities. From birth she displayed oligo-anuria which required dialytic substitutive therapy from the second day of life. At US scan both kidneys had normal diameters for gestational age slightly increased echogenicity and a reduced cortico-medullary differentiation. On the 20th day of life she had a surgical renal biopsy for the persistence of oligo-anuria, showing fetal glomeruli, without lymphocytic interstitial infiltrate, and normal tubuli without evidence of necrosis. She is now 16 months old and under automated peritoneal dialysis on a home dialysis program. The occurrence of chronic renal failure in strict relationship with maternal nimesulide assumption in this case is strongly suggestive for a pharmacological damage, either direct or mediated by renin angiotensin inhibition, and possibly modulated by genetic factors, likely to account for the different outcome of similarly treated patients. A cautious use of this drug as long term tocolytic should be recommended while waiting for ad hoc experimental and clinical evidences of safeness.
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PMID:[Neonatal chronic kidney failure associated with cyclo-oxygenase-2 inhibitors administered during pregnancy]. 1145 21

Angiotensin II (A-II) is the main effector of the renin-angiotensin system. A-II functions by binding its type 1 (AT1) receptors to cause vasoconstriction and retention of sodium and fluid. Several AT1 receptor antagonists-a group of drugs collectively called "sartans"-have been marketed during the past few years for treatment of hypertension and heart failure. At least 15 case reports describe oligohydramnios, fetal growth retardation, pulmonary hypoplasia, limb contractures, and calvarial hypoplasia in various combinations in association with maternal losartan, candesartan, valsartan, or telmisartan treatment during the second or third trimester of pregnancy. Stillbirth or neonatal death is frequent in these reports, and surviving infants may exhibit renal damage. The fetal abnormalities, which are strikingly similar to those produced by maternal treatment with angiotensin-converting enzyme (ACE) inhibitors during the second and third trimesters of pregnancy, are probably related to extreme sensitivity of the fetus to the hypotensive action of these drugs. Very little information is available regarding the outcome of human pregnancies in which the mother was treated with an AT1 receptor antagonist during the first trimester, but animal studies have not demonstrated teratogenic effects after maternal treatment with large doses of AT1 receptor antagonists during organogenesis. We conclude that pharmacological suppression of the fetal renin-angiotensin system through ACE inhibition or AT1 receptor blockade seems to disrupt fetal vascular perfusion and renal function. We recommend that maternal treatment with AT1 receptor antagonists be avoided during the second and third trimesters of pregnancy and that women who become pregnant while taking one of these medications be changed to an antihypertensive drug of a different class as soon as the pregnancy is recognized.
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PMID:Angiotensin II receptor antagonist treatment during pregnancy. 1566 52

Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (Potter phenotype). Absence or paucity of differentiated proximal tubules is the histopathological hallmark of the disease and may be associated with skull ossification defects. We studied 11 individuals with renal tubular dysgenesis, belonging to nine families, and found that they had homozygous or compound heterozygous mutations in the genes encoding renin, angiotensinogen, angiotensin converting enzyme or angiotensin II receptor type 1. We propose that renal lesions and early anuria result from chronic low perfusion pressure of the fetal kidney, a consequence of renin-angiotensin system inactivity. This is the first identification to our knowledge of a renal mendelian disorder linked to genetic defects in the renin-angiotensin system, highlighting the crucial role of the renin-angiotensin system in human kidney development.
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PMID:Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. 1611 25

Despite advances in treatment, twin-to-twin transfusion syndrome (TTTS) still carries a high risk for perinatal mortality and morbidity. Simple blood transfer from the donor to the recipient twin cannot explain all of the features of this disease, in particular the recipient's hypertensive cardiomyopathy. We report a case in which TTTS resulted in preterm delivery with early neonatal death of both twins, allowing assessment of the renin angiotensin system (RAS) status of each fetus, both by cord blood renin and aldosterone assay and by renal immunohistochemistry. The donor had severe oliguria/oligohydramnios, whereas the recipient, in addition to severe polyuria/polyhydramnios, had cardiomyopathy, atrioventricular regurgitation, and ascites. Although immunohistochemistry demonstrated that renal secretion of renin was up-regulated in the donor and down-regulated in the recipient, cord blood levels of renin and aldosterone were similar, with high renin levels in both twins. This observation supports the hypothesis that despite renal RAS down-regulation, the recipient is exposed to RAS effectors elaborated in the donor and transferred via placental shunts. This may contribute to cardiomyopathy and hypertension in the recipient, which cannot be accounted for by hypervolemia alone. We thus hypothesized that in TTTS, the recipient's hypertensive cardiomyopathy could be due to a mechanism similar to the classical model of hypertension referred to as "2 kidneys-1 clip." Thus the hypovolemic donor twin, comparable to the clipped kidney, produces vasoactive hormones that compromise the recipient, comparable to the normal kidney, causing hypertension and cardiomyopathy.
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PMID:Paradoxic activation of the renin-angiotensin system in twin-twin transfusion syndrome: an explanation for cardiovascular disturbances in the recipient. 1618 93

The renin-angiotensin system plays an important role in the regulation of blood pressure. The use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers both control hypertension by interruption of the production or action of angiotensin II, the major end-product of the renin-angiotensin system. The use of angiotensin converting enzyme inhibitors in pregnant women revealed serious and deleterious effects on fetal development including renal failure, renal dysplasia, hypotension, oligohydramnios, pulmonary hypoplasia, and hypocalvaria. The fetal effects of angiotensin converting enzyme inhibitors seem to be greatest during the 2nd and 3rd trimesters of pregnancy. The fetal effect of angiotensin converting enzyme inhibitors during the 1st trimester is controversial. These effects may represent the effect of hypoperfusion in the fetus and not a teratogenic effect. The effect of angiotensin receptor blockers is similar to converting enzyme inhibitors. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers should be avoided in all pregnant women. Alternative antihypertensive medications should be considered for use in women of childbearing years.
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PMID:Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists. 1642 19

Renal tubular dysgenesis is a clinical disorder that is observed in fetuses and characterized by the absence or poor development of proximal tubules, early onset and persistent oligohydramnios that leads to the Potter sequence, and skull ossification defects. It may be acquired during fetal development or inherited as an autosomal recessive disease. It was shown recently that autosomal recessive renal tubular dysgenesis is genetically heterogeneous and linked to mutations in the genes that encode components of the renin-angiotensin system. This study analyzed the clinical expression of the disease in 29 fetus/neonates from 18 unrelated families and evaluated changes in renal morphology and expression of the renin-angiotensin system. The disease was uniformly severe, with perinatal death in all cases as a result of persistent anuria and hypoxia related to pulmonary hypoplasia. Severe defects in proximal tubules were observed in all fetuses from 18 gestational weeks onward, and lesions also involved other tubular segments. They were associated with thickening of the renal arterial vasculature, from the arcuate to the afferent arteries. Renal renin expression was strikingly increased in 19 of 24 patients studied, from 13 families, whereas no renal renin was detected in four patients from three families. Angiotensinogen and angiotensin-converting enzyme were absent or present in only small amounts in the proximal tubule, in correlation with the severity of tubular abnormalities. No specific changes were detected in angiotensin II receptor expression. The severity and the early onset of the clinical and pathologic expression of the disease underline the major importance of this system in fetal kidney function and development in humans. The identification of the disease on the basis of precise histologic analysis and the research of the genetic defect now allow genetic counseling and early prenatal diagnosis.
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PMID:Renal tubular dysgenesis, a not uncommon autosomal recessive disorder leading to oligohydramnios: Role of the Renin-Angiotensin system. 1679 May 8


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