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Congenital renal tubular dysplasia and skull ossification defects similar to teratogenic effects of angiotensin converting enzyme (ACE) inhibitors.

ABSTRACT: An apparently autosomal recessive syndrome of congenital renal tubular dysplasia and skull ossification defects is described in five infants from two separate, consanguineous, Pakistani Muslim kindreds. The clinical, pathological, and radiological features are similar to the phenotype associated with fetal exposure to angiotensin converting enzyme (ACE) inhibitors: intrauterine growth retardation, skull ossification defects, and fetal/ neonatal anuric renal failure associated with renal tubular dysplasia. There was no fetal exposure to ACE inhibitors in the affected infants. Phenotypic similarities between these familial cases and those associated with ACE inhibition suggest an abnormality of the "renin-angiotensin-aldosterone" system (RAS). It is postulated that the molecular pathology in this uncommon autosomal recessive proximal renal tubular dysgenesis could be related to mutations of the gene systems governing the RAS.

SUBMITTER: Kumar D

PROVIDER: S-EPMC1050992 | biostudies-other | 1997 Jul

REPOSITORIES: biostudies-other

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Congenital renal tubular dysplasia and skull ossification defects similar to teratogenic effects of angiotensin converting enzyme (ACE) inhibitors.

Kumar D D Moss G G Primhak R R Coombs R R

Journal of medical genetics 19970701 7

An apparently autosomal recessive syndrome of congenital renal tubular dysplasia and skull ossification defects is described in five infants from two separate, consanguineous, Pakistani Muslim kindreds. The clinical, pathological, and radiological features are similar to the phenotype associated with fetal exposure to angiotensin converting enzyme (ACE) inhibitors: intrauterine growth retardation, skull ossification defects, and fetal/ neonatal anuric renal failure associated with renal tubular ...[more]

PMID: 9222960

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Project description:Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new therapeutic strategies for addressing age-related degenerative changes.

Project description:BackgroundRenin inhibitors (RIs) reduce blood pressure more than placebo, with the magnitude of this effect thought to be similar to that for angiotensin converting enzyme (ACE) inhibitors. However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. The effectiveness and safety of RIs compared to ACE inhibitors in treating hypertension is unknown.ObjectivesTo evaluate the benefits and harms of renin inhibitors compared to ACE inhibitors in people with primary hypertension.Search methodsThe Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to August 2020: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions.Selection criteriaWe included randomized, active-controlled, double-blinded studies (RCTs) with at least four weeks follow-up in people with primary hypertension, which compared renin inhibitors with ACE inhibitors and reported morbidity, mortality, adverse events or blood pressure outcomes. We excluded people with proven secondary hypertension.Data collection and analysisTwo review authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis.Main resultsWe include 11 RCTs involving 13,627 participants, with a mean baseline age from 51.5 to 74.2 years. Follow-up duration ranged from four weeks to 36.6 months. There was no difference between RIs and ACE inhibitors for the outcomes: all-cause mortality: risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.18; 5 RCTs, 5962 participants; low-certainty evidence; total myocardial infarction: RR 0.86, 95% CI 0.22 to 3.39; 2 RCTs, 957 participants; very low-certainty evidence; adverse events: RR 0.98, 95% CI 0.93 to 1.03; 10 RTCs, 6007 participants; moderate-certainty evidence; serious adverse events: RR 1.21, 95% CI 0.89 to 1.64; 10 RTCs, 6007 participants; low-certainty evidence; and withdrawal due to adverse effects: RR 0.85, 95% CI 0.68 to 1.06; 10 RTCs, 6008 participants; low-certainty evidence. No data were available for total cardiovascular events, heart failure, stroke, end-stage renal disease or change in heart rate. Low-certainty evidence suggested that RIs reduced systolic blood pressure: mean difference (MD) -1.72, 95% CI -2.47 to -0.97; 9 RCTs, 5001 participants; and diastolic blood pressure: MD -1.18, 95% CI -1.65 to -0.72; 9 RCTs, 5001 participants, to a greater extent than ACE inhibitors, but we judged this to be more likely due to bias than a true effect. AUTHORS' CONCLUSIONS: For the treatment of hypertension, we have low certainty that renin inhibitors (RI) and angiotensin converting enzyme (ACE) inhibitors do not differ for all-cause mortality and myocardial infarction. We have low to moderate certainty that they do not differ for adverse events. Small reductions in blood pressure with renin inhibitors compared to ACE inhibitors are of low certainty. More independent, large, long-term trials are needed to compare RIs with ACE inhibitors, particularly assessing morbidity and mortality outcomes, but also on blood pressure-lowering effect.

Dataset Information

Congenital renal tubular dysplasia and skull ossification defects similar to teratogenic effects of angiotensin converting enzyme (ACE) inhibitors.

Publications

Congenital renal tubular dysplasia and skull ossification defects similar to teratogenic effects of angiotensin converting enzyme (ACE) inhibitors.

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