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Reinhold Kreutz

Publications and source records attributed to Reinhold Kreutz.

At least 19 recordsLinked to original sources
PubMed2007

The G-231A polymorphism in the endothelin-A receptor gene is associated with lower aortic pressure in patients with dilated cardiomyopathy.

BACKGROUND: The endothelin system (ES) plays an important role in blood pressure (BP) regulation and also in the pathophysiology of idiopathic dilated cardiomyopathy (DCM). Recently, we demonstrated that a genetic polymorphism in the endothelin A (ET(A)) receptor gene was associated with survival in DCM patients. The aim of this study was to determine whether polymorphisms in the ET(A) receptor gene might be associated with the severity of DCM. METHODS: One hundred twenty-four consecutively recruited unrelated patients with DCM, who underwent a detailed phenotyping protocol, were genotyped for the ET(A) receptor G-231A polymorphism using a hybridization technique with allele-specific oligonucleotides. RESULTS: The exon 1 G-231A polymorphism of the ET(A) receptor gene, upstream of the translation start site, was significantly associated with directly measured intra-aortic pressure in that -231A allele carriers had significantly lower systolic (P = .0043), as well as mean (P = .0016) and diastolic (P = .0041) aortic pressure compared to noncarriers. The association of ET(A) G-231A with aortic pressure was independent from other factors such as prior medication, left ventricular end-diastolic diameter, age, gender, and New York Heart Association (NYHA) functional classification. However, no such association was seen for cuff BP and survival rates were not significantly different between -231A allele carriers and -231G homozygotes (log rank test, P = .66). No significant association with any other parameter investigated in the present study could be observed, even when men and women were analyzed separately. CONCLUSIONS: Our results suggest an association of genetic variation in the ET(A) receptor gene with aortic pressure in patients with DCM.

Aged↗
PubMed2007

Rat chromosome 19 transfer from SHR ameliorates hypertension, salt-sensitivity, cardiovascular and renal organ damage in salt-sensitive Dahl rats.

OBJECTIVES: Unlike Dahl salt-sensitive (SS) rats, some strains of spontaneously hypertensive (SHR) rats develop only minor organ damage even when exposed to high-salt diet. In previous linkage studies, we identified quantitative trait loci on rat chromosome 19 (RNO19) linked to the SHR allele suggesting a protective effect against salt-induced hypertensive organ damage in SS. METHODS: To test the relevance of this finding, we generated and characterized a consomic strain SS-19SHR in which RNO19 from SHR was introgressed into the susceptible background of SS. We compared the effects of low-salt (0.2% NaCl) and high-salt (4% NaCl) diet exposure for 8 weeks on the development of hypertension and target organ damage in male consomic and SS animals (n=14-20, each). RESULTS: Systolic blood pressure, relative left ventricular weight and urinary protein excretion were significantly lower in SS-19SHR compared to SS under both low-salt and high-salt diet (P < 0.05, respectively). Left ventricular atrial natriuretic peptide mRNA expression showed a more pronounced 4.5-fold increase in SS compared to SS-19 (two-fold) after high-salt (P < 0.05). In comparison to low diet, high-salt exposure induced a significant increase in vascular aortic hypertrophy index, left ventricular interstitial fibrosis (+210%) and perivascular fibrosis (+195%) in SS but not in consomic SS-19SHR (P < 0.05, respectively). CONCLUSIONS: These results demonstrate a strong protective effect of RNO19 from SHR on the development of hypertension, salt-sensitivity, cardiovascular and renal organ damage in SS. In particular, we demonstrate a genetic effect protecting against the development of cardiac fibrosis in salt-sensitive hypertension.

Animals↗
PubMed2006

Development of overt proteinuria in the Munich Wistar Frömter rat is suppressed by replacement of chromosome 6 in a consomic rat strain.

In a cross between the Munich Wistar Frömter (MWF) rat and spontaneously hypertensive rats (SHR), a major quantitative trait locus (QTL) was identified on rat chromosome 6 (RNO6) that demonstrated the strongest linkage to albuminuria among several QTL identified. The QTL represented the only locus that is linked to both early-onset albuminuria and increased renal interstitial fibrosis in adult animals. A consomic MWF-6(SHR) strain in which chromosome 6 from SHR was introgressed into the MWF background therefore was generated to test the relevance of this QTL. Phenotype analysis at 8 wk of age revealed that early onset of albuminuria in MWF with a 55-fold elevation of urinary albumin excretion compared with SHR (P < 0.0001) was completely abolished in MWF-6(SHR). Time-course analysis until week 24 demonstrated only a moderate increase of urinary albumin excretion in MWF-6(SHR), whereas MWF reached levels in the nephrotic range (16.6 +/- 3.5 versus 162.6 +/- 16.0 mg/24 h; P < 0.0001). At this age, analysis of glomerulosclerosis, tubulointerstitial damage, renal interstitial fibrosis, and renal collagen III mRNA expression revealed a significant improvement of all parameters in MWF-6(SHR) compared with MWF (P < 0.05). At 32 wk, MWF but not MWF-6(SHR) demonstrated overt proteinuria (354.6 +/- 37.6 versus 48.8 +/- 13.2; P < 0.0001), whereas serum urea, cholesterol, and triglyceride concentrations were lower and creatinine clearance was higher in MWF-6(SHR) compared with MWF (P < 0.05). Therefore, although albuminuria in MWF is determined by a complex interplay of several QTL, our data demonstrate that genetic exchange of one locus on RNO6 leads to marked suppression of early-onset albuminuria and renal damage in MWF.

Albuminuria↗
PubMed2006

Simulated weightlessness changes the cytoskeleton and extracellular matrix proteins in papillary thyroid carcinoma cells.

Studies of astronauts, experimental animals, and cells have shown that, after spaceflights, the function of the thyroid is altered by low-gravity conditions. The objective of this study was to investigate the cytoskeleton and extracellular matrix (ECM) protein synthesis of papillary thyroid cancer cells grown under zero g. We investigated alterations of ONCO-DG 1 cells exposed to simulated microgravity on a three-dimensional random-positioning machine (clinostat) for 30 min, 24 h, 48 h, 72 h, and 120 h (n=6, each group). ONCO-DG 1 cells grown under microgravity exhibited early alterations of the cytoskeleton and formed multicellular spheroids. The cytoskeleton was disintegrated, and nuclei showed morphological signs of apoptosis after 30 min. At this time, vimentin was increased. Vimentin and cytokeratin were highly disorganized, and microtubules (alpha-tubulin) did not display their typical radial array. After 48 h, the cytoskeletal changes were nearly reversed. The formation of multicellular spheroids continued. In parallel, the accumulation of ECM components, such as collagen types I and III, fibronectin, chondroitin sulfate, osteopontin, and CD44, increased. The levels of both transforming growth factor beta-1 (TGF-beta(1)) and TGF-beta receptor type II proteins were elevated from 24 h until 120 h clinorotation. Gene expression of TGF-beta(1) was clearly enhanced during culture under zero g. The amount of E-cadherin was enhanced time-dependently. We suggest that simulated weightlessness rapidly affects the cytoskeleton of papillary thyroid carcinoma cells and increases the amount of ECM proteins in a time-dependent manner.

Carcinoma, Papillary↗
PubMed2006

No association of the CYP3A5*1 allele with blood pressure and left ventricular mass and geometry: the KORA/MONICA Augsburg echocardiographic substudy.

A polymorphism in the cytochrome P450 3A CYP3A5 enzyme has been implicated in BP (blood pressure) control and arterial hypertension. Carriers of the CYP3A5*1 allele had high, whereas homozygous carriers of the CYP3A5*3 allele exhibit low, CYP3A5 expression in the kidney, where CYP3A5 represents the major CYP3A enzyme. The aim of the present study was to investigate the association of the CYP3A5*1 allele with BP, arterial hypertension, LVM [(left ventricular) mass] and LV geometry in a large Caucasian-population-based cohort. We compared BP, LVM and the prevalence of hypertension between carriers (CYP3A5*1/*1 and CYP3A5*1/*3 genotypes) and non-carriers (CYP3A5*3/*3 genotype) of the CYP3A5*1 allele in the echocardiographic substudy of the third MONICA (MONItoring trends and determinants in CArdiovascular disease) Augsburg survey. After exclusion of 269 individuals who were taking antihypertensive medication, 530 women and 554 men were available for analysis, revealing allele frequencies of 5.8 and 94.2% for the CYP3A5*1 and CYP3A5*3 alleles respectively. Overall, the presence of the CYP3A5*1 allele exhibited no effect on systolic or diastolic BP in either gender. One-third of the individuals in this cohort were hypertensive (BP > or =140/90 mmHg), and the genotype distribution between normotensive and hypertensive individuals revealed no association between CYP3A5*1 and hypertension after adjustment for age, BMI and gender (odds ratio, 1.02; P=0.92). Moreover, no effect of CYP3A5*1 on LVM, thickness of the septal and posterior wall and LV end-diastolic diameter was found. We conclude that CYP3A5*1 exhibits no significant effect on BP, LVM and LV geometry in the KORA/MONICA echocardiographic substudy.

Adult↗
PubMed2006

Pharmacokinetics and safety of olmesartan medoxomil in combination with glibenclamide in healthy volunteers.

OBJECTIVE: To investigate the pharmacokinetic interactions, safety, and tolerability of the combination of olmesartan medoxomil with glibenclamide. METHODS: In an open, three-way crossover, phase I trial, 18 healthy adults entered three randomly ordered, seven-day treatment periods. The three treatments comprised once daily administration of (1) olmesartan 20 mg, (2) olmesartan 20 mg plus glibenclamide 3.5 mg, or (3) glibenclamide 3.5 mg. RESULTS: The combination of olmesartan with glibenclamide did not influence the bioequivalence of the area under the plasma-concentration time curve at steady state during one dosing interval 0 to tau = 24 hours (AUCss,tau) or the maximum steady-state concentration (Css,max) of both substances. Mean AUCss,tau values for olmesartan were 2594.8 ng h/ml for olmesartan alone and 2443.7 ng h/ml in combination with glibenclamide; the corresponding Css,max values were 479.3 ng/ml and 462.7 ng/ml, respectively. For glibenclamide, the mean AUCss,tau values were 525.7 ng x h/ml for monotherapy and 518.7 ng x h/ml for its combination with olmesartan. The median time to reach Css,max (tmax) for glibenclamide was shifted from 2.0 h to 1.0 h when combined with olmesartan, whereas the median tmax values for olmesartan remained unchanged at 1.5 h. During combined treatment with olmesartan plus glibenclamide, no adverse event occurred, and the medications were well tolerated. CONCLUSION: With the exception of a slight shift of tmax values for glibenclamide, the concomitant administration of olmesartan medoxomil with glibenclamide had no significant effects on the steady-state pharmacokinetics of either agent. This provides the pharmacokinetic rationale for clinical studies to test the combination therapy of patients with hypertension and type-2 diabetes mellitus with both compounds.

Adolescent↗
PubMed2006

Genetic low nephron number hypertension is associated with dysregulation of the hepatic and renal insulin-like growth factor system during nephrogenesis.

OBJECTIVE: Low nephron number may represent a major determinant of human primary hypertension in adult life. This hypothesis is supported by a genetic rat model, namely the Munich-Wistar-Frömter (MWF) rat, which demonstrates an inherited deficit in nephron number and the development of spontaneous hypertension. Insulin-like growth factor (IGF) I and II exert endocrine and paracrine effects that are required for normal growth and nephron development. We tested the hypothesis that low nephron number is already present during fetal development, and the expression pattern of important molecules of the IGF system is altered in MWF rat during the critical period of kidney development. METHODS: We compared MWF and normal Wistar rats during nephrogenesis at day 19 of fetal development (E19) and adult rats at postnatal day 100 (D100). Histomorphometric analysis was performed by stereological methods. Quantitative messenger RNA and protein expression was determined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: At E19, glomerular density (-32%) and hepatic mRNA (-48%) and protein (-18%) expression of IGF-I were decreased (P < 0.05, respectively), whereas renal mRNA expression of IGF-II receptor (+52%) and IGF binding protein 3 (+113%) were increased in MWF compared with Wistar rats (P < 0.05, respectively). Systolic blood pressure, urinary albumin excretion, and mean glomerular area were significantly elevated in MWF compared with Wistar rats at D100 (P < 0.05, respectively). CONCLUSIONS: The fetal expression of IGF system molecules in the MWF rat model points towards a link between the decreased availability of active IGF-I and IGF-II and the fetal development of low nephron number, with manifestation of genetic hypertension in adult life.

Animals↗
PubMed2006

Physiology of local renin-angiotensin systems.

Since the first identification of renin by Tigerstedt and Bergmann in 1898, the renin-angiotensin system (RAS) has been extensively studied. The current view of the system is characterized by an increased complexity, as evidenced by the discovery of new functional components and pathways of the RAS. In recent years, the pathophysiological implications of the system have been the main focus of attention, and inhibitors of the RAS such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin (ANG) II receptor blockers have become important clinical tools in the treatment of cardiovascular and renal diseases such as hypertension, heart failure, and diabetic nephropathy. Nevertheless, the tissue RAS also plays an important role in mediating diverse physiological functions. These focus not only on the classical actions of ANG on the cardiovascular system, namely, the maintenance of cardiovascular homeostasis, but also on other functions. Recently, the research efforts studying these noncardiovascular effects of the RAS have intensified, and a large body of data are now available to support the existence of numerous organ-based RAS exerting diverse physiological effects. ANG II has direct effects at the cellular level and can influence, for example, cell growth and differentiation, but also may play a role as a mediator of apoptosis. These universal paracrine and autocrine actions may be important in many organ systems and can mediate important physiological stimuli. Transgenic overexpression and knock-out strategies of RAS genes in animals have also shown a central functional role of the RAS in prenatal development. Taken together, these findings may become increasingly important in the study of organ physiology but also for a fresh look at the implications of these findings for organ pathophysiology.

Animals↗
PubMed2006

Pharmacokinetics of olmesartan medoxomil plus hydrochlorothiazide combination in healthy subjects.

BACKGROUND: Hypertension treatment guidelines recommend combination therapy with diuretics and other antihypertensive agents, including angiotensin II type 1 (AT1) receptor antagonists. This trial investigated the possibility of pharmacokinetic interactions between the AT1 receptor antagonist olmesartan medoxomil and the thiazide diuretic hydrochlorothiazide in healthy subjects. METHODS: Twenty-four healthy normotensive adult male subjects underwent three consecutive 7-day treatment periods (A, B and C, respectively) during which they were randomised to receive: olmesartan medoxomil 20 mg once daily (regimen A), hydrochlorothiazide 25 mg once daily (regimen B), or olmesartan medoxomil 20 mg once daily plus hydrochlorothiazide 25 mg once daily (regimen C). Treatment periods were separated by washouts of 7-14 days. The primary pharmacokinetic parameters evaluated were: the area under the plasma concentration versus time curve at steady state (AUCss,tau), the maximum plasma concentration at steady state (Css,max), and the time at which Css,max occurred (tmax). RESULTS: Complete data sets from 17 subjects were available for pharmacokinetic analyses. Mean concentration versus time profiles were similar for monotherapy and combination treatment for both olmesartan (the active metabolite of olmesartan medoxomil) and hydrochlorothiazide. For olmesartan, comparison of monotherapy with combination therapy showed that for AUCss,tau and Css,max point estimates were close to unity, demonstrating bioequivalence. For hydrochlorothiazide, combination therapy resulted in decreases in AUCss,tau and Css,max of approximately 10% versus monotherapy; nevertheless, since 90% CIs were within the acceptance range, bioequivalence was proven. Median tmax values for olmesartan and hydrochlorothiazide for periods A, B and C were identical, indicating bioequivalence. Both olmesartan medoxomil and hydrochlorothiazide were well tolerated. CONCLUSION: These results show that there is little or no potential for a clinically relevant pharmacokinetic interaction between olmesartan medoxomil 20 mg and hydrochlorothiazide 25 mg, and therefore dosage adjustment should not be necessary when they are co-administered.

Adolescent↗
PubMed2005

Expression and response to angiotensin-converting enzyme inhibition of matrix metalloproteinases 2 and 9 in renal glomerular damage in young transgenic rats with renin-dependent hypertension.

Extracellular matrix expansion in the glomerular mesangium contributes to the development of glomerulosclerosis and chronic renal disease in arterial hypertension. Transforming growth factor-beta1 (TGF-beta1), matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMPs) are involved in this process. Conflicting data are reported on the effects of angiotensin II (Ang II) and the response to angiotensin-converting enzyme inhibition on MMPs and TIMPs in early stages of hypertensive glomerular damage. We therefore investigated the effects of Ang II-dependent hypertension on MMP-2, MMP-9, TIMP-1, and TIMP-2 in isolated glomeruli of 8-week-old homozygous male rats overexpressing the mouse Ren2 gene [TGR(mRen2)27]. At this age, systolic blood pressure was already significantly elevated in Ren2 compared with Sprague-Dawley (SD) rats (197 +/- 38 versus 125 +/- 16 mm Hg, p < 0.01). Ren2 exhibited renal damage as determined by increased urinary albumin excretion, focal glomerulosclerosis, mesangial matrix expansion, and alpha-smooth muscle actin deposition. Quantification of mRNA levels in isolated glomeruli by real-time polymerase chain reaction showed a significant increase of TGF-beta1, a 2.3- and a 2.6-fold increase of MMP-2 and TIMP-1 in Ren2 compared with SD (p < 0.01, respectively) and no strain differences for TIMP-2. In contrast, MMP-9 mRNA expression was markedly suppressed to 10% of control levels in Ren2 (p < 0.01). Early treatment with ramipril completely prevented renal damage in Ren2 and restored mRNA expression of TGF-beta1, MMP-2, and TIMP-1 to SD control levels. Interestingly, down-regulation of MMP-9 mRNA, protein, and activity was not affected by ramipril, indicating that the protective effect of this compound is not attributable to restoration of MMP-9 in the glomerulus.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Increase of fibronectin and osteopontin in porcine hearts following ischemia and reperfusion.

Following a severe ischemic injury or myocardial infarction, the extracellular matrix (ECM) of the heart is involved in pathophysiological conditions such as dilatation and cardiac dysfunction. Osteopontin (OPN) has been shown to interact with fibronectin suggesting its possible role in matrix organization, stability and wound healing. There is increased expression of OPN in several tissues in response to injury. Therefore, we tested the hypothesis that acute ischemia (2 h), followed by reperfusion (4 h) may induce early OPN and fibronectin in an isolated hemoperfused working porcine heart model. Twenty hearts were prepared and connected to a perfusion system. After 1 h of perfusion, these hearts were randomized to two groups: ten infarcted (MI, ramus circumflexus) and ten non-infarcted hearts (C). In addition, cardiac fibroblasts derived from infarcted, remote and control myocardium were investigated. In both groups, the heart rate, electrolytes, pH, blood gases, and lactate remained similar. The LVEDP and perfusion pressure of MI hearts increased significantly (P<0.05). The total fibronectin and OPN volume contents were clearly elevated in the infarct area. The matrix metalloproteinases (MMP-1 and MMP-8), fibronectin, OPN, TGF-beta1 proteins and the mRNAs for fibronectin, TGF-beta1, and OPN were significantly elevated in the infarct area as compared to the remote area and the non-infarcted hearts. Simultaneously, circulating carboxyterminal propeptide of type I procollagen (PICP) was released in the perfusion medium (threefold versus C). Fibroblast-like cells originating from the infarct area exhibited an enhanced OPN and fibronectin gene and protein expression compared to fibroblasts derived from control myocardium. Our data demonstrate the early appearance of the MMPs (increased collagen degrading enzymes) and PICP (a collagen synthesis marker) following ischemia and reperfusion. Moreover, OPN, fibronectin and TGF-beta1 protein and gene expression are elevated after ischemia and reperfusion in the ex vivo working hemoperfused porcine heart model.

Animals↗
PubMed2005

Increased transient receptor potential channel TRPC3 expression in spontaneously hypertensive rats.

BACKGROUND: Disturbances in the regulation of cytosolic calcium concentration have been attributed to primary hypertension, but the role of calcium-permeable transient receptor potential canonical channel 3 (TRPC3) has not yet been evaluated in primary hypertension. METHODS: Expression of TRPC3 was determined using in-cell Western assay. Evaluation of RNA interference for the downregulation of a specific gene in cells by small interfering RNA was performed. Measurements of cytosolic calcium were carried out using the fluorescent dye fura2. RESULTS: Expression of TRPC3 was significantly increased in monocytes from spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto rats (WKY). Transplasmamembrane calcium influx and thapsigargin-induced sustained calcium increase were significantly higher in SHR compared with WKY. In the presence of the TRP channel blocker SKF-96365 these differences were no longer observed. Specific TRPC3-knockdown by transfection of monocytes from SHR with small interfering RNA significantly reduced TRPC3 expression, trans-plasma membrane calcium influx, and thapsigargin-induced sustained calcium increase. CONCLUSIONS: This study shows, for the first time, increased TRPC3 channel expression and increased TRPC3-related calcium influx in SHR.

Animals↗
PubMed2005

Low-dose lithium combined with captopril prevents stroke and improves survival in salt-loaded, stroke-prone spontaneously hypertensive rats.

OBJECTIVE: A number of potential interactions between angiotensin-converting enzyme inhibitors and lithium have been described in the literature. In the present study, we investigated the effects of a low-dose combination treatment with lithium and captopril on survival and stroke prevention in salt-loaded, stroke-prone spontaneously hypertensive rats (SHRSP). METHODS: Eight-week-old saline-drinking SHRSP (n = 21 per group) were treated with vehicle, LiCl (1 mmol/kg per day), captopril (25 mg/kg per day) and captopril plus LiCl for up to 37 weeks. Body weight, salt water intake blood pressure and mortality were recorded throughout the experimental period. Plasma renin activity, plasma lithium concentration and urinary excretion of albumin, sodium and potassium were measured at different time points. RESULTS: Captopril treatment doubled the life expectancy when compared with vehicle-treated rats. Lithium alone had minor effects on survival but led to a dramatic increase in survival when added to captopril (mean survival time > 237 versus 147 days, P < 0.001). Systolic blood pressure increased with age in all treatment groups but was comparable in the captopril-treated and the captopril-plus-lithium-treated groups. Plasma renin activity as well as urinary sodium and potassium excretion did not differ between both groups. In the captopril group a striking fivefold increase of albuminuria occurred between 14 and 26 weeks of age, while this progression was completely abolished by the addition of lithium. CONCLUSIONS: Our results demonstrate that the addition of lithium to captopril dramatically prolong the effects of the angiotensin-converting enzyme inhibitor on survival in salt-loaded SHRSP. This effect was independent of a reduction in blood pressure.

Albuminuria↗
PubMed2005

The role of the cytochrome P450 3A5 enzyme for blood pressure regulation in the general Caucasian population.

Cytochrome P450 3A (CYP3A) enzymes are important for drug metabolism in gut and liver. The CYP3A5 isoenzyme is also expressed in the kidney and has been implicated in renal sodium reabsorption and blood pressure regulation. Its expression and activity is strongly linked to a polymorphism (i.e. 6986G > A). Thus, appreciable expression is found in carriers of the CYP3A5*1 (6986A) but not in homozygous carriers of the CYP3A5*3 (6986G) allele. We tested whether the presence of CYP3A5*1 affects blood pressure in Caucasian individuals who were enrolled in the Prevention of REnal and Vascular ENd stage Disease (PREVEND) study. In addition, we evaluated whether the genetic effect of CYP3A5*1 on blood pressure is modulated by sodium intake. CYP3A5*1 was found in 13.3% (901 individuals) of the cohort (6777 individuals). Diastolic blood pressure was not affected by CYP3A5*1. Overall, systolic and pulse pressure were significantly lower in carriers of CYP3A5*1, both after univariate analysis adjusted for age (P = 0.012 and P = 0.008) and in logistic regression analysis (P = 0.015 and P = 0.012). The effect on systolic blood pressure was significantly modulated by sodium intake (P = 0.038). In separate analysis according to gender, CYP3A5*1 accounted for a significant age adjusted decrease in systolic blood pressure (-1.6 mmHg, P = 0.04) and pulse pressure (-1.2 mmHg, P = 0.04) in females but not in men. The present study demonstrates that the CYP3A5*1 allele affects systolic blood pressure and pulse pressure in the general population. Its role in hypertensive disease and potential gender differences should be investigated in further studies.

Adult↗
PubMed2005

An expectation-maximization-likelihood-ratio test for handling missing data: application in experimental crosses.

The mapping of quantitative trait loci (QTL) is an important research question in animal and human studies. Missing data are common in such study settings, and ignoring such missing data may result in biased estimates of the genotypic effect and thus may eventually lead to errant results and incorrect inferences. In this article, we developed an expectation-maximization (EM)-likelihood-ratio test (LRT) in QTL mapping. Simulation studies based on two different types of phylogenetic models revealed that the EM-LRT, a statistical technique that uses EM-based parameter estimates in the presence of missing data, offers a greater statistical power compared with the ordinary analysis-of-variance (ANOVA)-based test, which discards incomplete data. We applied both the EM-LRT and the ANOVA-based test in a real data set collected from F2 intercross studies of inbred mouse strains. It was found that the EM-LRT makes an optimal use of the observed data and its advantages over the ANOVA F-test are more pronounced when more missing data are present. The EM-LRT method may have important implications in QTL mapping in experimental crosses.

Algorithms↗
PubMed2004

Genetic linkage of albuminuria and renal injury in Dahl salt-sensitive rats on a high-salt diet: comparison with spontaneously hypertensive rats.

Our aim was to study the effects of high-salt diet on the genetics of albuminuria and renal injury in the Dahl salt-sensitive (SS) rat. We compared SS with salt-resistant spontaneously hypertensive rats (SHR) and with genetically related salt-sensitive stroke-prone SHR (SHRSP). Moreover, we performed genome-wide linkage analysis to identify quantitative trait loci (QTL) contributing to salt-induced renal injury in an F2 population derived from SS and SHR (n = 230). In response to high-salt diet SS and SHRSP developed a striking increase in systolic blood pressure, urinary albumin excretion (UAE), and renal damage indices compared with SHR. Both SHRSP and SS developed severe glomerulosclerosis, whereas microangiopathy, tubulointerstitial fibrosis, and inflammation were more pronounced in SHRSP. We detected two QTL with significant linkage to UAE on rat chromosomes (RNO) 6 and 19. Comparison with the recently identified salt-independent UAE QTL in young animals revealed that the UAE QTL on RNO6 is unique to high-salt conditions, whereas RNO19 plays a significant role during both low- and high-salt conditions. Some F2 animals demonstrated severe microangiopathy and tubulointerstitial injury, which exceeded the degree observed in the parental SS strain. Three loci demonstrated suggestive linkage to these phenotypes on RNO3, RNO5, and RNO20, whereas no linkage to glomerular damage was found. Further analyses at these loci indicated that the severity of renal injury was attributable to the SHR allele. Our data suggest that the SHR genetic background confers greater susceptibility for the development of microangiopathy and tubulointerstitial injury in salt-sensitive hypertension than the SS background.

Albuminuria↗
PubMed2004

Genetic kininogen deficiency contributes to aortic aneurysm formation but not to atherosclerosis.

Brown Norway (BN) and BN Katholiek (BN/Ka) rat strains are both susceptible to develop lesions in the internal elastic lamina (IEL) of the aorta. BN/Ka rats are characterized by a single point mutation in the kininogen gene leading to deficiency in high- and low-molecular-weight kininogen. Recently, a suggestive quantitative trait locus for lesions in the IEL of the abdominal aorta was identified in an F2 intercross between Dahl salt-sensitive (SS) and BN rats, implicating kininogen as a positional candidate gene. Therefore, BN and BN/Ka rat strains represent ideal model organisms with which to study the contribution of kininogen to the genetic predisposition to IEL lesion formation and to characterize the early events underlying vascular remodeling. Here we present data demonstrating that genetic kininogen deficiency promotes the formation of aneurysms in the abdominal aorta but not the development of atherosclerosis upon 12-wk treatment with an atherogenic diet. Aneurysm formation was associated with an enhanced elastolysis, increased expression of MMP-2 and MMP-3, downregulation of TIMP-4, and with FasL- and caspase-3-mediated apoptosis. Kininogen-deficient animals also featured changes in plasma cytokines compatible with apoptotic vascular damage, i.e., upregulation of IFN-gamma and downregulation of GM-CSF and IL-1beta. Finally, in response to atherogenic diet, kininogen-deficient animals developed an increase in HDL/total cholesterol index, pronounced fatty liver and heart degeneration, and lipid depositions in aortic media without atherosclerotic plaque formation. These findings suggest that genetic kininogen deficiency renders vascular tissue prone to aneurysmatic but not to atherosclerotic lesions.

Abdomen↗