The kidney as a determinant of genetic hypertension: evidence from renal transplantation studies.
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Animals↗
Biomedical subjects
Rainer Rettig
Publications and source records attributed to Rainer Rettig.
Interaction between factor V Leiden and serum LDL cholesterol increases the risk of atherosclerosis.
OBJECTIVES: We investigated the association between the factor V Leiden gene variant and carotid atherosclerosis in a cross-sectional study and explored possible associations between this gene variant and coronary artery disease (CAD) in a case-control study. METHODS: The presence (n=1696) or absence (n=703) of carotid atherosclerosis were sonographically assessed among participants of the population-based Study of Health in Pomerania (SHIP). The case-control study included 1021 patients with severe CAD and 2791 healthy SHIP participants. The factor V Leiden gene variant was determined by PCR and MnlI digestion. RESULTS: Multivariable analyses revealed no independent association between the factor V Leiden gene variant per se and carotid atherosclerosis or CAD. In the cross-sectional study, there was an interaction between the factor V Leiden gene variant and serum LDL cholesterol in non-diabetics with respect to the risk of carotid atherosclerosis. In the case-control study a similar interaction was found for CAD. In both studies the atherosclerotic risk increased with rising serum LDL cholesterol concentrations in carriers of the factor V Leiden gene variant. CONCLUSION: The co-existence between the factor V Leiden gene variant and high serum LDL cholesterol is independently associated with the risk of atherosclerosis.
Adult↗
Renin-angiotensin system and haemostasis gene polymorphisms and outcome after coronary artery bypass graft surgery.
BACKGROUND: Coronary artery bypass graft surgery is associated with a considerable 2-year mortality rate. Gene polymorphisms of the renin-angiotensin system may be associated with the risk of hypertension and cardiovascular disease. The angiotensin I-converting enzyme DD genotype has recently been identified as independent predictor of the outcome after coronary artery bypass graft surgery. Genetic factors of the clotting system may be related to the risk of myocardial infarction and restenosis after coronary interventions. The aims of the present study were to investigate whether gene polymorphisms of the renin-angiotensin system (angiotensinogen 235 M/T, angiotensin II type 1 receptor 1166 A/C) or the clotting system (glycoprotein IIIa PlA1/PlA2 and factor V Leiden 1691 G/A) are associated with the outcome after coronary artery bypass grafting. METHODS: A study population of 247 patients was followed-up 2 years after coronary artery bypass graft surgery. The primary end-point was total mortality. The secondary end-point was mortality from cardiac cause or the need for myocardial revascularization (percutaneous coronary interventions or recurrent surgery) during follow-up. Geno typing was performed by polymerase chain reaction- and restriction fragment length polymorphism-based techniques. RESULTS: An older age and the non-use of the internal mammary artery graft were identified as independent predictors of the primary end-point after coronary artery bypass grafting. A decreased left ventricular ejection fraction was an independent predictor for the secondary end-point. No association was found between any of the genetic factors and the outcomes after coronary artery bypass graft surgery in the main factor regression models. However, the angiotensin II type 1 receptor 1166 A/C gene polymorphism modulated the effects of age on the primary end-point, and the angiotensinogen 235 M/T gene polymorphism modulated the effects of age on the secondary end-point. CONCLUSION: We conclude that there are interactions between the angiotensin II type 1 receptor 1166 A/C as well as the angiotensinogen 235 M/T gene polymorphism and age with respect to the outcome after coronary artery bypass graft surgery. The glycoprotein IIIa PlA1/PlA2 and the factor V Leiden 1691 G/A gene polymorphisms were not associated with mid-term mortality or cardiac morbidity after coronary artery bypass grafting.
Adult↗
Influence of neonatal sympathectomy on proximal renal resistance artery function in spontaneously hypertensive rats.
Renal transplantation experiments have shown that the kidney contributes to chronic sympathectomy-induced arterial pressure reduction in spontaneously hypertensive rats (SHR). The underlying mechanisms are currently unclear but may include alterations in the function of small renal arteries. Neonatal SHR were sympathectomized by intraperitoneal guanethidine injections and removal of adrenal medullary tissue. Controls were sham- or hydralazine-treated. At 12 weeks of age, distal interlobar artery segments were investigated using small-vessel wire myography. Vessels from sympathectomized animals showed increased sensitivity to noradrenaline (NE). Vasopressin- and endothelin-1-induced vasoconstriction was similar in all groups (as reflected by the pD(2), i.e. -logEC(50), where EC(50) is the molar concentration of agonist eliciting a half-maximal response). Maximum vasopressin-induced tension was similar in all groups while endothelin-1-induced maximum tension was significantly higher in sympathectomized than in sham-treated SHR. The sensitivity of NE-induced vasoconstriction to extracellular Ca(2+) did not differ between groups while sensitivity to L-type Ca(2+) channel activation was significantly higher in both sympathectomized and hydralazine-treated animals than in sham-treated animals. Endothelium-dependent and independent vasodilation were similar in all groups. Sequential blockade of NO-synthase and cyclooxygenase had similar effects in all groups. In conclusion, neonatal sympathectomy does not induce any changes in the function of isolated proximal renal resistance arteries from SHR that could explain the blood pressure lowering effect of a kidney graft from sympathectomized SHR.
Animals↗
Interactions between the sympathetic nervous system and the kidneys in arterial hypertension.
Elevated sympathetic activity changes renal function and accelerates the development of hypertension. Principles of sympatho-renal interactions in chronic hypertension are reviewed. Alterations in the ontogeny of the sympathetic nervous system and the kidney, inherited abnormalities in sensory receptor function and exaggerated responsiveness to mental stress contribute to inappropriately high sympathetic activity in primary or essential hypertension. Careful characterization of clinical study populations shows that elevated sympathetic activity and "essential" hypertension are not unequivocally associated. Prospective clinical studies which investigate a broader array of physiological functions and experiments in recombinant inbred rodents with less traumatic nerve recording techniques than currently available will help to define under which conditions elevated sympathetic activity is indeed a cause of primary hypertension. Signals arising from the kidney which activate the renin-angiotensin system and afferent renal nerves increase sympathetic activity. These mechanisms importantly contribute to the pathogenesis of hypertension secondary to renal artery stenosis and end-stage renal disease.
Angiotensin II↗
Candidate genetic markers and the risk of restenosis after coronary angioplasty.
The aim of the present study was to test for possible associations between candidate gene polymorphisms and the risk of restenosis and recurrent restenosis after percutaneous transluminal coronary angioplasty (PTCA) without stenting. We followed up 511 PTCA patients, and restenosis and recurrent restenosis were defined according to angiographical criteria. Genotyping of the beta-fibrinogen -455 G/A, glycoprotein (GP) IIIa PlA1/PlA2, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, factor V Leiden 1691 G/A, tumour necrosis factor alpha (TNFalpha) -238 G/A, TNFalpha -308 G/A, interleukin (IL)-1alpha -889 C/T, IL-1beta -511 C/T, methylenetetrahydrofolate reductase (MTHFR) 677 C/T and endothelial nitric oxide synthase (eNOS) 4 b/a gene polymorphisms was performed by PCR and restriction-fragment-length-polymorphism-based techniques. One hundred and sixty patients (31.3%) developed restenosis and in 130 of these patients, of whom 123 were available for analysis, a second PTCA without stenting was performed. Of these patients, 35 (28.5%) developed recurrent restenosis. None of the investigated genotypes were associated with the risk of restenosis or recurrent restenosis after PTCA. The degree of stenosis before and immediately after PTCA and the severity of the lesion were independent predictors for restenosis after PTCA. In conclusion, there was no association between the beta-fibrinogen -455 G/A, GP IIIa PlA1/A2, PAI-1 4G/5G, factor V Leiden 1691 G/A, TNFalpha -238 G/A, TNFalpha -308 G/A, IL-1alpha -889 C/T, the IL-1beta -511 C/T, MTHFR 677 C/T and eNOS 4 b/a gene polymorphisms and the risk of restenosis after PTCA as well as recurrent restenosis after repeated PTCA.
Angioplasty, Balloon, Coronary↗
Analysis of arterial pressure regulating systems in renal post-transplantation hypertension.
OBJECTIVE: To investigate if blood volume expansion, increased sodium retention, changes in neurohumoral arterial pressure control, or altered extrarenal resistance vessel function contribute to the development of renal post-transplantation hypertension. METHODS: F1-hybrids (F1H) obtained from crossing spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats received either an SHR or an F1H kidney graft. Groups consisted of 8-12 animals and were investigated between days 1 and 14 after renal transplantation in three sets of experiments including arterial pressure recordings, plasma volume measurements, metabolic studies, and small vessel myography. RESULTS: Two days after completion of bilateral nephrectomy, arterial pressure was elevated by 15-20 mmHg in recipients of an SHR kidney, compared with syngeneically transplanted controls. There was no evidence for increased sodium and fluid retention during the early development of renal post-transplantation hypertension despite a 35% reduced creatinine clearance in recipients of an SHR kidney. The plasma renin-angiotensin-aldosterone system was similarly suppressed in both recipients of an SHR kidney and controls. The arterial pressure response to ganglionic blockade did not differ between groups and there was no evidence for changes in extrarenal resistance vessel function, which could be involved in the genesis of this form of hypertension. CONCLUSIONS: None of the investigated mechanisms was altered in a way that might help to explain the rapid and consistent development of hypertension in recipients of an SHR kidney. We conclude that post-transplantation hypertension in recipients of an SHR kidney is due to mechanisms other than those investigated in the present study.
Aldosterone↗
Thyroid function and carotid wall thickness.
Decreased serum TSH levels predict vascular mortality in older people. There is a need to investigate mechanisms that could explain this association. This study was designed to investigate the relationship between thyroid function and the carotid intima-media thickness (IMT). The Study of Health in Pomerania is a population-based survey in Germany. Data from 2086 individuals at least 45 yr old with carotid ultrasound and without known thyroid disorders were analyzed. Twenty-nine participants (1.4%) had elevated serum TSH levels, 300 (14.4%) had decreased serum TSH levels, and 12 (0.6%) participants were hyperthyroid. A linear relationship between thyroid function and IMT was found. The highest IMT values were observed in participants with hyperthyroidism, the lowest in subjects with elevated serum TSH levels (P < 0.01). A multivariable regression analysis identified thyroid function as an independent risk factor for increased IMT. Other risk factors for increased IMT included male gender, advanced age, diabetes mellitus, current smoking, and the use of antihypertensive medication; increased pulse pressure, serum low-density cholesterol, and total cholesterol/high-density lipoprotein ratio; as well as a decreased heart rate and a positive history of myocardial infarction. We conclude that there is an independent association between thyroid function and the IMT of the carotid artery.
Carotid Arteries↗
Sodium/lithium countertransport and intracellular calcium concentration in patients with essential hypertension and coronary heart disease.
The present study was designed to test the hypothesis that enhanced intracellular calcium signalling and increased sodium/lithium countertransport (Na(+)/Li(+) CT) activity may be associated with coronary heart disease (CHD) in non-diabetic patients with essential hypertension. Platelet-activating factor (PAF)-evoked rises in the intracellular calcium concentration ([Ca(2+)](i)) were measured in Epstein-Barr-virus-immortalized lymphoblasts from 62 hypertensive patients with CHD and 34 patients without CHD. Na(+)/Li(+) CT activity was assessed in erythrocytes from 80 hypertensive patients with CHD and 46 patients without CHD. Baseline values of unstimulated and PAF-stimulated [Ca(2+)](i) were not significantly different between hypertensive subjects with (baseline, 126+/-5 nmol/l; stimulated, 550+/-43 nmol/l) and without (baseline, 125+/-5 nmol/l; stimulated, 654+/-105 nmol/l) CHD. Similarly, Na(+)/Li(+) CT activity was not significantly different between the two groups (patients with CHD, 219+/-8 micromol x l(-1) x h(-1); patients without CHD, 234+/-10 micromol x l(-1) x h(-1)). We conclude that intracellular signal transduction, as indicated by PAF-induced rises in [Ca(2+)](i) and Na(+)/Li(+) CT activity, is not associated with an increased risk of CHD in non-diabetic patients with essential hypertension.
Aged↗
Preoperative plasma fibrinogen levels predict mortality after coronary artery bypass grafting.
This study was designed to investigate whether plasma fibrinogen levels as well as the beta-fibrinogen -455 G/A genotype are associated with outcome after coronary artery bypass graft (CABG) operation. We enrolled 249 consecutive CAD patients one day before they underwent a CABG operation. Data from 220 patients with available plasma fibrinogen levels were analyzed. The primary end-point was total mortality, the secondary end-point mortality from cardiac causes or the need for myocardial revascularization. The 2-year total mortality was 9.1% in the entire cohort. Multivariable analysis revealed an independent relationship between the primary end-point and preoperative plasma fibrinogen levels but not the beta-fibrinogen -455 G/A genotype. Neither preoperative plasma fibrinogen levels nor the beta-fibrinogen -455 G/A genotype could predict the secondary end-point. We conclude, that elevated preoperative plasma fibrinogen levels, but not the beta-fibrinogen -455 G/A genotype predict the total mortality after CABG operation.
Adult↗
Angiotensinogen M235T gene polymorphism and recurrent restenosis after repeated percutaneous transluminal coronary angiography.
The present study was designed to prospectively test the hypothesis that gene polymorphisms of the renin-angiotensin system are associated with recurrent restenosis after repeated percutaneous transluminal coronary angioplasty. Five hundred and eleven patients after first successful angioplasty were characterized with respect to the angiotensinogen M235T, angiotensin-converting enzyme insertion/deletion and angiotensin II type 1 receptor A1166C gene polymorphisms. In 164 of these patients repeated angioplasty on a restenotic lesion was performed. After repeated angioplasty, 46 patients had recurrent restenosis as defined by a greater than 50% progression of residual stenosis. In the recurrent restenosis group there was a statistically significant higher percentage of patients receiving cholesterol-lowering drugs compared with the group of patients without recurrent restenosis. The two groups of patients did not differ with respect to procedural and angiographic parameters. There were significantly more carriers of the angiotensinogen 235T allele in the recurrent restenosis group than in the control group without recurrent restenosis. No differences between the two groups were found with respect to the other gene polymorphisms investigated. According to the results of a multifactorial analysis of variance, only the 235T allele of the angiotensinogen gene and not cholesterol drug therapy independently affected the increase of stenosis at follow-up angiography. In conclusion, the angiotensinogen 235T allele may be an independent predictor for recurrent restenosis after repeated angioplasty.
Adult↗
Long-term arterial pressure in spontaneously hypertensive rats is set by the kidney.
OBJECTIVES: We investigated whether arterial pressure in spontaneously hypertensive rats (SHR) can be normalized by a kidney graft from normotensive histocompatible donors. In addition, the effect of differential genetic predisposition to hypertension of recipients of an SHR kidney on the development of post-transplantation hypertension was studied. METHODS: SHR were transplanted with a kidney from congenic rats (BB.1K) homozygous for a 2 cM segment of SHR chromosome 20, including the major histocompatibility complex class Ia and class II genes. BB.1K and F1 hybrids (F1H, SHR x Wistar-Kyoto rats) were transplanted with an SHR kidney and the development of renal post-transplantation hypertension was monitored. RESULTS: Thirty days after renal transplantation, mean arterial pressure (MAP) was 116 +/- 4 mmHg in SHR with a BB.1K kidney (n = 8) versus 168 +/- 2 mmHg in sham-operated SHR (n = 10); P < 0.001. Cumulative renal sodium balance (mmol/100 g body weight) over 21 days after bilateral nephrectomy was 6.8 +/- 0.6 in SHR with a BB.1K kidney versus 10.8 +/- 1.6 in sham-operated SHR (P < 0.05). Within 60 days of transplantation, MAP increased in BB.1K and in F1H transplanted with an SHR kidney (n = 7 per group) by 38 +/- 5 mmHg and 43 +/- 8 mmHg, respectively. CONCLUSIONS: In SHR, arterial pressure can be normalized by a kidney graft from normotensive donors. The genetic predisposition of the recipients to hypertension does not modify the rate and the extent of the arterial pressure rise induced by an SHR kidney graft.
Animals↗
Association studies between the angiotensin-converting enzyme insertion/deletion polymorphism and hypertension: still interesting?
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DNA Transposable Elements↗
Sympathetic-renal interaction in chronic arterial pressure control.
The effects of neonatal sympathectomy of donors or recipients on posttransplantation arterial pressure were investigated in spontaneously hypertensive rats (SHR) by renal transplantation experiments. Conscious mean arterial pressure (MAP) and renal vascular resistance were 136 +/- 1 mmHg and 15.5 +/- 1.2 mmHg x ml(-1) x min x g in sympathectomized SHR (n = 8) vs. 158 +/- 4 mmHg (P < 0.001) and 20.8 +/- 1.1 mmHg x ml(-1) x min x g (P < 0.05) in controls (n = 10). Seven weeks after transplantation of a kidney from neonatally sympathectomized SHR donors, MAP in SHR recipients (n = 10) was 20 mmHg lower than in controls transplanted with a kidney from hydralazine-treated SHR (n = 10) (P < 0.05) associated with reduced sodium sensitivity of MAP. Neonatal sympathectomy also lowered MAP in F1-hybrids (F1H; SHR x Wistar-Kyoto rats). Within 6 wk after transplantation, renal grafts from untreated SHR increased MAP by 20 mmHg in sympathectomized F1H (n = 10) and by 35 mmHg in sham-treated F1H (n = 8) (P < 0.05). Neonatal sympathectomy induces chronic changes in SHR kidney function leading to a MAP reduction even when extrarenal sympathetic tone is restored. Generalized reduction in sympathetic tone resets the kidney-fluid system to reduced MAP and blunts the extent of arterial pressure rise induced by an SHR kidney graft.
Animals↗
Angiotensin I-converting enzyme insertion/deletion polymorphism and cardiac mortality and morbidity after coronary artery bypass graft surgery.
STUDY OBJECTIVES: This study was designed to evaluate whether the insertion (I)/deletion (D) polymorphism of the angiotensin I-converting enzyme (ACE) gene is associated with mortality and cardiac morbidity after coronary artery bypass graft surgery (CABG). METHODS AND RESULTS: The ACE I/D genotype was determined in 249 consecutive patients who underwent CABG. Follow-up information (after 2 years) was obtained in 247 patients (99.2%). The primary end point was total mortality; the secondary end point was mortality from cardiac reasons, or the need for myocardial revascularization (coronary angioplasty or recurrent CABG) during follow-up. At follow-up, total mortality was 9.7% (all patients). None of the 51 patients with the ACE II genotype, 14 of 125 patients with the ACE ID genotype (11.2%), and 10 of 71 with the ACE DD genotype (14.1%) died during follow-up (p < 0.05). The ACE DD genotype, older age, diabetes mellitus, decreased left ventricular ejection fraction, and lack of internal mammary artery graft were independently related to an increased mortality after CABG. The incidence of the secondary end point was 14.5% (all patients): ACE II, 5.8%; ACE ID, 9.4%; ACE DD, 30.3% (p < 0.05). The ACE DD genotype and the presence of a left main coronary artery stenosis >or= 50% were independent predictors for the secondary end point. CONCLUSION: The ACE DD genotype is associated with increased midterm mortality and cardiac morbidity after CABG.
Adult↗