Search PubMed⌕ Search

Biomedical subjects

M E Cooper

Publications and source records attributed to M E Cooper.

At least 19 recordsLinked to original sources
PubMed2006

Developmental expression of ACE2 in the SHR kidney: a role in hypertension?

The abnormal development of the intrarenal renin-angiotensin system (RAS) is thought contribute to adult-onset hypertension in the spontaneously hypertensive rat (SHR). Angiotensin-converting enzyme 2 (ACE2) is a novel enzyme with complementary actions to that of ACE. Recent studies have shown that ACE2 expression is reduced in the adult SHR. However, its regulation in pre-hypertensive animals is unknown. In this study, we examine the developmental expression of ACE2 in the rodent kidney and its temporal expression, as it relates to the development of hypertension in the SHR model. Kidneys from SHR and normotensive Wistar Kyoto (WKY) rats (n=8-12/group) at birth, 6 weeks of age, and adulthood (80 days) were examined. Gene expression and activity of ACE2 were determined by real-time reverse transcription-polymerase chain reaction and quenched fluorescence assays, respectively. Renal expression was localized by in situ hybridization and immunohistochemistry. The expression and ACE2 activity are significantly increased in the SHR kidney at birth. With the onset of hypertension, the tubular expression of ACE2 falls in SHR compared to WKY and remains reduced in the adult SHR kidney. Glomerular expression is paradoxically increased in the SHR glomerulus. The overall developmental pattern of ACE2 expression in the SHR kidney is also modified, with declining expression over the course of renal development. The developmental pattern of ACE2 expression in the SHR kidney is altered before the onset of hypertension, consistent with the key role of the RAS in the pathogenesis of adult-onset hypertension. Further research is required to distinguish the contribution of these changes to the development and progression of hypertension in this model.

Angiotensin-Converting Enzyme 2↗
PubMed2006

Anaemia in diabetes: Is there a rationale to TREAT?

BACKGROUND: Anaemia is a common finding in patients with diabetes, particularly in those with overt nephropathy or renal impairment. In tertiary clinics, at least one outpatient in five with diabetes has anaemia, for whom it constitutes a significant additional burden. DISCUSSION: Anaemia is associated with an increased risk of diabetic complications including nephropathy, retinopathy and macrovascular disease. Anaemia may also be significant in determining the outcome of heart failure and hypoxia-induced organ damage in diabetes. While several factors contribute to the increased prevalence of anaemia in diabetes, the failure of the kidney to increase erythropoietin in response to falling haemoglobin appears to be the dominant factor. Although there is a clear rationale for correcting anaemia in people with diabetes, it remains to be established whether this will lead to improved outcomes. Moreover, the balance of risks, costs, and benefits remains to be established in patients with diabetes. The Trial to Reduce Cardiovascular Events with Aranesp (darbepoetin alpha) Therapy (TREAT) is a randomised controlled trial designed to determine the impact of anaemia correction on mortality and non-fatal cardiovascular events in patients with type 2 diabetes and stage 3-4 nephropathy. CONCLUSION: It is anticipated that TREAT will help to define the optimal approach to the management of anaemia in diabetes.

Anemia↗
PubMed2006

Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation.

AIMS/HYPOTHESIS: It is postulated that peroxisome proliferator-activated receptor alpha agonists confer cardiovascular benefits in diabetes, independently of their effects on lipid metabolism. We investigated putative mechanisms responsible for these anti-atherogenic effects in an in vivo model of diabetes-associated atherosclerosis. MATERIALS AND METHODS: Control and streptozotocin-induced diabetic apolipoprotein-deficient mice received gemfibrozil (100 mg kg(-1) day(-1)) or no treatment for 20 weeks. Aortic plaque deposition was assessed by Sudan IV staining and subsequent en face quantification. Superoxide production was measured using lucigenin-enhanced chemiluminescence. Markers of pathways including inflammation and oxidative stress were measured using real-time RT-PCR. RESULTS: No significant effect of gemfibrozil was observed on glycated haemoglobin, cholesterol or insulin in diabetic mice. Diabetes was associated with a three-fold increase in plaque area and a significant increase in NADPH-dependent superoxide compared with control mice. Gemfibrozil significantly attenuated plaque area and superoxide production in diabetic mice. In addition, gemfibrozil reduced the expression of the genes encoding the NADPH oxidase subunits p47phox, gp91phox and Rac-1. In addition, gemfibrozil reduced the expression of the genes encoding nuclear factor kappa B (NF-kappaB) subunit, p65, the NF-kappaB-dependent chemokine monocyte chemoattractant protein-1, and tissue factor. CONCLUSIONS/INTERPRETATIONS: This study demonstrates that gemfibrozil exerts anti-atherogenic actions, independently of changes in cholesterol and glucose metabolism. Such findings emphasise the possible usefulness of fibrates such as gemfibrozil in a setting of atherosclerosis even in the absence of dyslipidaemia.

Angiotensins↗
PubMed2006

Contributions of PTCH gene variants to isolated cleft lip and palate.

OBJECTIVE: Mutations in patched (PTCH) cause the nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin syndrome. Nevoid basal cell carcinoma syndrome may present with developmental anomalies, including rib and craniofacial abnormalities, and predisposes to several tumor types, including basal cell carcinoma and medulloblastoma. Cleft palate is found in 4% of individuals with nevoid basal cell carcinoma syndrome. Because there might be specific sequence alterations in PTCH that limit expression to orofacial clefting, a genetic study of PTCH was undertaken in cases with cleft lip and/or palate (CL/P) known not to have nevoid basal cell carcinoma syndrome. RESULTS: Seven new normal variants spread along the entire gene and three missense mutations were found among cases with cleft lip and/or palate. One of these variants (P295S) was not found in any of 1188 control samples. A second variant was found in a case and also in 1 of 1119 controls. The third missense (S827G) was found in 5 of 1369 cases and in 5 of 1104 controls and is likely a rare normal variant. Linkage and linkage desequilibrium also was assessed using normal variants in and adjacent to the PTCH gene in 220 families (1776 individuals), each with two or more individuals with isolated clefting. Although no statistically significant evidence of linkage (multipoint HLOD peak = 2.36) was uncovered, there was borderline evidence of significant transmission distortion for one haplotype of two single nucleotide polymorphisms located within the PTCH gene (p = .08). CONCLUSION: Missense mutations in PTCH may be rare causes of isolated cleft lip and/or palate. An as yet unidentified variant near PTCH may act as a modifier of cleft lip and/or palate.

Adenine↗
PubMed2006

Diabetic nephropathy: from mechanisms to rational therapies.

Diabetic nephropathy is a microvascular complication of diabetes. Specifically, it represents a major cause of morbidity and mortality in type 1 and type 2 diabetic subjects and has become the leading cause of end-stage renal disease in the Western world. Diabetic nephropathy appears to develop as a result of interactions between environmental insults and genetic susceptibility. Indeed, hyperglycemia is a clinical prerequisite for this complication, but it should be noted that only a subset of diabetic subjects will ultimately develop nephropathy. Over recent decades, cellular and molecular mechanisms underlying diabetic nephropathy have been increasingly delineated. In particular, diabetic kidney disease appears to occur as a result of the deleterious effects of both metabolic and hemodynamic insults, which at the cellular level lead to the activation of intracellular signaling pathways and transcription factors, thus triggering the production/release of cytokines, chemokines and growth factors, which mediate and/or amplify the renal damage. This ultimately leads to the structural and functional features characteristic of diabetic kidney disease. In the present review we summarize the evidence for key mediators of injury, which appear to be excellent treatment targets in diabetic nephropathy. The targets include various vasoactive hormones, the biochemical processes of the advanced glycation and protein kinase C. Furthermore, we review current and potentially new renoprotective therapies in the setting of diabetes.

Angiotensin II↗
PubMed2005

Polymorphisms in the gene encoding angiotensin I converting enzyme 2 and diabetic nephropathy.

AIMS/HYPOTHESIS: Substantial evidence exists for the involvement of the renin-angiotensin system (RAS) in diabetic nephropathy. Angiotensin I converting enzyme 2 (ACE2), a new component of the RAS, has been implicated in kidney disease, hypertension and cardiac function. Based on this, the aim of the present study was to evaluate whether variations in ACE2 are associated with diabetic nephropathy. MATERIALS AND METHODS: We used a cross-sectional, case-control study design to investigate 823 Finnish type 1 diabetic patients (365 with and 458 without nephropathy). Five single-nucleotide polymorphisms (SNPs) were genotyped using TaqMan technology. Haplotypes were estimated using PHASE software, and haplotype frequency differences were analysed using a chi(2)-test-based tool. RESULTS: None of the ACE2 polymorphisms was associated with diabetic nephropathy, and this finding was supported by the haplotype analysis. The ACE2 polymorphisms were not associated with blood pressure, BMI or HbA(1)c. CONCLUSIONS/INTERPRETATION: In Finnish type 1 diabetic patients, ACE2 polymorphisms are not associated with diabetic nephropathy or any studied risk factor for this complication. Further studies are necessary to assess a minor effect of ACE2.

Adult↗
PubMed2005

Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2.

BACKGROUND: Angiotensin converting enzyme (ACE) 2 is a recently identified homologue of ACE that may counterregulate the actions of angiotensin (Ang) II by facilitating its breakdown to Ang 1-7. The renin-angiotensin system (RAS) has been implicated in the pathogenesis of cirrhosis but the role of ACE2 in liver disease is not known. AIMS: This study examined the effects of liver injury on ACE2 expression and activity in experimental hepatic fibrosis and human cirrhosis, and the effects of Ang 1-7 on vascular tone in cirrhotic rat aorta. METHODS: In sham operated and bile duct ligated (BDL) rats, quantitative reverse transcriptase-polymerase chain reaction was used to assess hepatic ACE2 mRNA, and western blotting and immunohistochemistry to quantify and localise ACE2 protein. ACE2 activity was quantified by quenched fluorescent substrate assay. Similar studies were performed in normal human liver and in hepatitis C cirrhosis. RESULTS: ACE2 mRNA was detectable at low levels in rat liver and increased following BDL (363-fold; p < 0.01). ACE2 protein increased after BDL (23.5-fold; p < 0.05) as did ACE2 activity (fourfold; p < 0.05). In human cirrhotic liver, gene (>30-fold), protein expression (97-fold), and activity of ACE2 (2.4 fold) were increased compared with controls (all p < 0.01). In healthy livers, ACE2 was confined to endothelial cells, occasional bile ducts, and perivenular hepatocytes but in both BDL and human cirrhosis there was widespread parenchymal expression of ACE2 protein. Exposure of cultured human hepatocytes to hypoxia led to increased ACE2 expression. In preconstricted rat aorta, Ang 1-7 alone did not affect vascular tone but it significantly enhanced acetylcholine mediated vasodilatation in cirrhotic vessels. CONCLUSIONS: ACE2 expression is significantly increased in liver injury in both humans and rat, possibly in response to increasing hepatocellular hypoxia, and may modulate RAS activity in cirrhosis.

Angiotensin I↗
PubMed2005

Role of the renin-angiotensin system in the endocrine pancreas: implications for the development of diabetes.

Activation of the renin-angiotensin system has a pivotal role in the pathogenesis of diabetic complications. However, recent evidence suggests that it may also contribute to the development of diabetes itself. In the endocrine pancreas, all the components of an active renin-angiotensin system are present, which modulate a range of activities including local blood flow, hormone release and prostaglandin synthesis. In both types 1 and 2 diabetes, there is an up-regulation of its expression and activity in the endocrine pancreas. Whether these changes have a direct pathogenetic role or reflect a response to local stress or tissue injury remains to be established. Angiotensin-mediated increases in oxidative stress, inflammation and free fatty acids levels potentially contribute to beta-cell dysfunction in diabetes. In addition, activation of the renin-angiotensin system appears to potentiate the action of other pathogenic pathways including glucotoxicity, lipotoxicity and advanced glycation. In experimental models of type 2 diabetes, blockade of the renin-angiotensin system with angiotensin converting enzyme inhibitors or angiotensin receptor antagonists results in the improvement of islet structure and function. Moreover, the incidence of de novo diabetes appears to be significantly reduced by blockade of the renin-angiotensin system in clinical studies. At least two large controlled trials are currently underway to study the role of renin-angiotensin system in the development of diabetes. It is hoped that these studies will demonstrate the true potential of the blockade of the renin-angiotensin system for the prevention of diabetes.

Angiotensin I↗
PubMed2005

Adverse effects of left ventricular hypertrophy in the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan (RENAAL) study.

AIMS/HYPOTHESIS: We explored the impact of baseline left ventricular hypertrophy (LVH) and losartan treatment on renal and cardiovascular (CV) events in 1,513 patients from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, which studied the effects of losartan on the progression of renal disease and/or death in patients with type 2 diabetes and nephropathy. MATERIALS AND METHODS: LVH was assessed using ECG criteria (Cornell product and/or Sokolow-Lyon voltage). The risk of renal or CV events was determined by a proportional hazards model fit with treatment allocation and presence of LVH. Covariates at baseline included age, sex, systolic BP, mean arterial pressure, pulse, proteinuria, serum creatinine, albumin and haemoglobin. RESULTS: A total of 187 subjects (12%) had LVH at baseline. Treatment with losartan resulted in a significant decrease in the Cornell product (-6.2%) and Sokolow-Lyon voltage (-6.3%). LVH was shown to be significantly associated with the primary endpoint, which was a composite of doubling of serum creatinine (DSCR), endstage renal disease (ESRD) or death (hazard ratio [HR]=1.44, p=0.011), as well as with the composite renal endpoint of DSCR/ESRD (HR=1.42, p=0.031) and CV events (HR=1.68, p=0.001). Losartan treatment of patients with LVH decreased the CV as well as renal risk to a level similar to that of patients without LVH. CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes and nephropathy, LVH is associated with significantly increased risk of CV events and the progression of kidney disease. Importantly, in patients with LVH, losartan reduced the CV as well as the renal risk to a level similar to that seen in subjects without LVH.

Aged↗
PubMed2005

Poor prognosis in proteinuric type 2 diabetic patients with retinopathy: insights from the RENAAL study.

BACKGROUND: Retinopathy is the clinical hallmark of generalized microangiopathy in diabetes. AIM: To examine the relation of this abnormality to end-stage renal disease (ESRD) and death in type 2 diabetes. DESIGN: Retrospective analysis. METHODS: Of 1513 type 2 diabetic patients with nephropathy participating in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, 1456 (96.5%) were assessed at baseline by ophthalmoscopy or fundus photography. RENAAL was a multinational double masked, randomized, placebo-controlled intervention study, whose primary end-point was the composite of a doubling of the baseline serum creatinine concentration, end-stage renal disease (ESRD) or death. RESULTS: Of those assessed at baseline, 65% had diabetic retinopathy. Patients with retinopathy had higher systolic blood pressure, albuminuria and lower glomerular filtration rate (GFR), haemoglobin and serum albumin values than those without. In univariate analyses, the presence of retinopathy was associated with a 44% increase in the primary composite end-point (hazard ratio 1.44, 95%CI 1.22-1.70, p < 0.001). Patients with retinopathy had a 52% increase in doubling of serum creatinine (p < 0.001), a 47% increased risk of ESRD (p = 0.002) and a 33% increase in risk of death (p = 0.026) compared to those without. In multivariate analyses, the presence of retinopathy was associated with a 23% increase (p = 0.015) in the primary composite end-point and a 22% increase in ESRD or death (p = 0.038). DISCUSSION: The presence of diabetic retinopathy at baseline is associated with more proteinuria, lower GFR, and a higher risk for ESRD and death in type 2 diabetic patients.

Albuminuria↗
PubMed2005

Tubular changes in early diabetic nephropathy.

Far from being bystanders in diabetic nephropathy, changes in the proximal tubule are important for the development of progressive diabetic kidney disease. The proximal tubule is uniquely susceptible to a variety of metabolic and hemodynamic factors associated with diabetes. Renal function and prognosis correlate better with structural lesions in the tubuli and cortical interstitium than with classical glomerular changes of diabetic nephropathy. The proximal tubules show a variety of poorly characterized changes, which have led to the notion that tubular damage represents a "final common pathway" for proteinuric renal injury. However, tubular hypertrophy, reduced organic ion transport, and other tubular changes reviewed in this paper, are already apparent before the onset of proteinuria in diabetes. Indeed, increased tubuloglomerular feedback and defective uptake and lysosomal processing may independently contribute to hyperfiltration and urinary protein loss, respectively. This finding does not mean that glomerular or vascular dysfunction do not contribute to progressive nephropathy. However, although subdividing the nephron for the purposes of analysis and scientific discovery may be useful, the interactions between tubule, glomerulus, and interstitium are likely key to the understanding of complex disorders such as diabetic nephropathy. From this "holonephric" point of view, an understanding of the changes in the diabetic tubule forms an important component to the understanding of kidney disease in diabetes.

Diabetic Nephropathies↗
PubMed2005

Tuftelin, mutans streptococci, and dental caries susceptibility.

The purpose of this study was to identify genetic factors that contribute to dental caries susceptibility, either alone or in combination with environmental factors. Dental examinations were performed and buccal swab samples collected from 3- to 5-year-old children with at least 4 surfaces of decay, or with no evidence of decay. SNP assays for each of 6 candidate genes were performed for all cases and controls. Chi-square analysis and regression analysis were used for the evaluation of individual gene effects, environmental effects, and gene-environment interactions. There were no significant associations between single candidate genes and caries susceptibility. Levels of S. mutans were positively and Lactobacilli were negatively associated with caries. Regression analysis revealed a significant interaction between tuftelin and S. mutans, with 26.8% of the variation in dmfs explained by the interaction. Future research will focus on the identification of these additional factors and the development of functional assays so that these interactions can be better understood.

Chi-Square Distribution↗
PubMed2005

The role of AGEs and AGE inhibitors in diabetic cardiovascular disease.

Prolonged hyperglycemia, dyslipidemia and oxidative stress in diabetes result in the production and accumulation of AGEs. It is now clear that AGEs contribute to the development and progression of cardiovascular disease in diabetes, as well as other complications. AGEs are thought to act through receptor-independent and dependent mechanisms to promote vascular damage, fibrosis and inflammation associated with accelerated atherogenesis. As a result, novel therapeutic agents to reduce the accumulation of AGEs in diabetes have gained interest as potential cardioprotective approaches. A variety of agents have been developed which are examined in detail in this review. These include aminoguanidine, ALT-946, pyridoxamine, benfotiamine, OPB-9195, alagebrium chloride, N-phenacylthiazolium bromide and LR-90. In addition, it has been demonstrated that a number of established therapies have the ability to reduce the accumulation of AGEs in diabetes including ACE inhibitors, angiotensin receptor antagonists, metformin, peroxisome proliferators receptor agonists, metal chelators and some antioxidants. The fact that many of these inhibitors of AGEs are effective in experimental models, despite their disparate mechanisms of action, supports the keystone role of AGEs in diabetic vascular damage. Nonetheless, the clinical utility of AGE inhibition remains to be firmly established. Optimal metabolic and blood pressure control, that is achieved early and sustained indefinitely, remains the best recourse for inhibition of AGEs until more specific interventions become a clinical reality.

Animals↗
PubMed2004

Early vitamin E supplementation attenuates diabetes-associated vascular dysfunction and the rise in protein kinase C-beta in mesenteric artery and ameliorates wall stiffness in femoral artery of Wistar rats.

AIMS/HYPOTHESIS: The impact of early vitamin E supplementation on vascular function in diabetes remains unresolved. Therefore, we examined the effects of vitamin E on functional and structural parameters and on chemical markers that are disturbed in diabetes in mesenteric and femoral arteries. METHODS: Segments of both arteries, taken from control and 8-week-old streptozotocin diabetic Wistar rats that were treated or not with vitamin E, were mounted on wire and pressure myographs, after which endothelium-dependent and -independent vasodilation was assessed. Passive mechanical wall properties and the localisation and levels of protein kinase C (PKC)-beta(2) and AGE were evaluated in these vessels. RESULTS: Vitamin E supplementation was associated with improved endothelium-dependent and -independent vasodilatation in mesenteric arteries from diabetic rats. Impaired endothelium-dependent vasodilatation in diabetic mesenteric vessels was associated with PKC-beta(2) up-regulation and this was prevented by vitamin E supplementation. Increased AGE accumulation and plasma isoprostane levels in diabetic rats were not changed by vitamin E. In the femoral artery, vitamin E supplementation had no effect on endothelium-dependent or -independent vasodilatation, but did prevent the wall stiffening associated with diabetes. CONCLUSIONS/INTERPRETATION: Early vitamin E supplementation has a beneficial effect on diabetes-induced endothelial dysfunction in resistance arteries. This benefit may arise from a direct effect on smooth muscle function, as a result of inhibition of the PKC-beta(2) isoform by vitamin E.

Acetylcholine↗
PubMed2004

Targeted scan of fifteen regions for nonsyndromic cleft lip and palate in Filipino families.

Cleft lip with or without cleft palate (CL/P) is a congenital anomaly with variable birth prevalence based on geographic origins, with the highest rates commonly found in Asian populations. About 70% of cases are nonsyndromic (NS), in which the affected individual has no other abnormalities. NS CL/P is a complex disorder with genetic and environmental effects and no specific genetic loci yet confirmed. Fifteen candidate regions were examined for linkage to NS CL/P. Regions were chosen based on previous suggestive linkage and/or association in human families, or suggestive animal model data. Polymorphic markers in these regions were genotyped for analysis on 36 Filipino families comprised of 126 affected and 218 unaffected individuals. An additional 70 families with 149 affecteds were used for replication of suggestive results. Parametric (LOD score) and nonparametric (SIMIBD) linkage analyses were performed as well as transmission disequilibrium test (TDT) analysis. Five markers yielded suggestive results from the 36 families. The parametric LOD scores for the MSX1-CA and D4S1629 were >1.0 and the SIMIBD P values for D6S1029 and RFC1 are suggestive (<0.06), while the SIMIBD P value of 0.01 for TGFA was significant. Since the Msx1 mouse knockout has cleft palate and MSX1 mutations have been found in rare cases of syndromic CL/P, this locus is especially plausible for linkage. Previous studies have also found linkage of NS CL/P to 4q31 and 6p23. These regions contain several candidate genes, including AP2 at 6p23 and FGF2, BMPR1B, and MADH1 at 4q31. TGFA has both linkage and linkage disequilibrium data supporting it as a candidate gene for NS CL/P. While no region was definitively confirmed for linkage to NS CL/P, the data do support further investigation using larger sample sizes and candidate gene studies at 2p13.2, 4p16.2, 4q31, 6p23, and 16q22-24.

Chromosome Mapping↗
PubMed2004

Identification of angiotensin converting enzyme 2 in the rodent retina.

PURPOSE: An active renin-angiotensin system has been found in the retina of rats and humans. Angiotensin-converting enzyme 2 (ACE2) is a recently discovered enzymatic homologue of Angiotensin-converting enzyme (ACE) that may be an important new component of the renin-angiotensin system (RAS). This study assesses the involvement of ACE2 in the normal and diabetic rodent retina and its modulation by ACE inhibition. METHODS: Sprague-Dawley rats were randomised into three groups, control, diabetes, and diabetes plus ramipril, with diabetes induced with the cell toxin streptozocin and the study run for 24 weeks. ACE2 and ACE gene levels were measured using quantitative real-time polymerase chain reaction (QRT-PCR), ACE2 protein expression was confirmed by Western blotting, and ACE and ACE2 catalytic activity were measured using specific activity assays in the rat retina. Localisation of ACE2 mRNA and protein were determined by in situ hybridisation and immunohistochemistry, respectively. RESULTS: ACE mRNA levels were decreased to approximately 50% in the diabetic retina, but ACE2 mRNA levels were not significantly changed. ACE but not ACE2 gene expression was influenced by ramipril treatment. Following immunostaining, both ACE2 and ACE protein were localised predominantly to the inner nuclear layer (INL) but also to photoreceptors. In the diabetic retina, ACE enzyme activity was decreased, whereas ACE2 enzyme activity was increased. CONCLUSIONS: This study has identified ACE2 gene and catalytically active protein in the rodent retina. In diabetes, the major changes were a decrease in ACE but an increase in ACE2 enzymatic activity. The ACE inhibitor ramipril did not reduce ACE2 enzymatic activity.

Angiotensin-Converting Enzyme 2↗