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Biomedical subjects

Mark E Cooper

Publications and source records attributed to Mark E Cooper.

At least 37 records · Page 2Linked to original sources
PubMed2005

Diabetes induces Na/H exchange activity and hypertrophy of rat mesenteric but not basilar arteries.

Experimental hyperglycemia produces a marked hypertrophic response in rat mesenteric arteries, accompanied by activation of Na/H exchange (NHE) in medial smooth muscle. This study asked if other vascular beds are similarly affected by examining the hypertrophic and NHE response of the basilar artery. Sections of mesenteric and basilar arteries from adult rats were analysed by standard morphometric techniques at 1 and 3 weeks after streptozotocin injection. NHE activity was assessed as changes in intracellular pH in isolated intact vessels using concurrent myography and fluorescence spectroscopy. Mesenteric arteries showed a significant increase in lumenal (47%), medial (51%) and adventitial (17%) area. In contrast, these parameters were not increased in basilar arteries from the same set of animals. Maximal NHE activity was significantly increased at 1 week (24%) and 3 weeks (20%) in mesenteric arteries, but in basilar arteries there was no change in basal intracellular pH, maximal NHE activity or kinetic properties of the transporter. NHE plays a central role in vascular changes in diabetes. As the mesenteric hypertrophy is amenable to therapeutic intervention these findings add further to the potential of NHE as a therapeutic target for ameliorating vascular disease in diabetes.

Animals↗
PubMed2005

Modulation of soluble receptor for advanced glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy.

Recent studies have identified that first-line renoprotective agents that interrupt the renin-angiotensin system not only reduce BP but also can attenuate advanced glycation end product (AGE) accumulation. This study used in vitro, preclinical, and human approaches to explore the potential effects of these agents on the modulation of the receptor for AGE (RAGE). Bovine aortic endothelial cells that were exposed to the angiotensin-converting enzyme inhibitor (ACEi) ramiprilat in the presence of high glucose demonstrated a significant increase in soluble RAGE (sRAGE) secreted into the medium. In streptozotocin-induced diabetic rats, ramipril treatment (ACEi) at 3 mg/L for 24 wk reduced the accumulation of skin collagen-linked carboxymethyllysine and pentosidine, as well as circulating and renal AGE. Renal gene upregulation of total RAGE (all three splice variants) was observed in ACEi-treated animals. There was a specific increase in the gene expression of the splice variant C-truncated RAGE (sRAGE). There were also increases in sRAGE protein identified within renal cells with ACEi treatment, which showed AGE-binding ability. This was associated with decreases in renal full-length RAGE protein from ACEi-treated rats. Decreases in plasma soluble RAGE that were significantly increased by ACEi treatment were also identified in diabetic rats. Similarly, there was a significant increase in plasma sRAGE in patients who had type 1 diabetes and were treated with the ACEi perindopril. Complexes between sRAGE and carboxymethyllysine were identified in human and rodent diabetic plasma. It is postulated that ACE inhibition reduces the accumulation of AGE in diabetes partly by increasing the production and secretion of sRAGE into plasma.

Alternative Splicing↗
PubMed2005

Anemia with impaired erythropoietin response in diabetic patients.

BACKGROUND: Diabetes mellitus is associated with an increased prevalence of anemia, particularly in patients with nephropathy. We undertook this survey to determine the relationship between anemia and the renal production of erythropoietin in patients with diabetes mellitus. METHODS: The clinical data of 722 patients were obtained, including markers of diabetic complications. Erythropoietin levels were measured in the same samples. Patients with a full blood cell count, iron indexes, and renal function within the normal range (n = 151) were used to define the reference range for this population. Anemic patients who had erythropoietin levels within this range were defined as having an "inappropriate erythropoietin response to anemia." RESULTS: Of the 722 patients, 168 (23.3%) had anemia, of whom 130 (77.4%) had erythropoietin levels inappropriately within the normal range. Although 55.4% of anemic patients had moderate renal impairment, erythropoietin levels were also inappropriately low in 69.2% of anemic patients with normal renal function. However, most of these patients (17 of 26) had diabetic kidney disease, as denoted by albuminuria. CONCLUSIONS: The failure to produce erythropoietin in response to a declining hemoglobin level is a common contributor to anemia in patients with diabetes mellitus. This seems to be a manifestation of diabetic kidney disease, in the presence or absence of renal impairment.

Aged↗
PubMed2005

Myocardial infarction increases ACE2 expression in rat and humans.

AIMS: Angiotensin converting enzyme (ACE) 2 catalyses the cleavage of angiotensin (Ang) I to Ang 1-9 and of Ang II to Ang 1-7. ACE2 deficiency impairs cardiac contractility and upregulates hypoxia-induced genes, suggesting a link with myocardial ischaemia. We studied the expression of ACE2 after myocardial infarction (MI) in the rat as well as in human failing hearts. METHODS AND RESULTS: Rats were killed at days 1, 3, and 28 after MI, or treated for 4 weeks with the ACE inhibitor ramipril (1 mg/kg). Cardiac gene and protein expression of ACE and ACE2 were assessed by quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry/activity assays/in vitro autoradiography, respectively. Both ACE (P = 0.022) and ACE2 (P = 0.015) mRNA increased in the border/infarct area compared with the viable area at day 3 after MI. By day 28, increases in ACE (P = 0.005) and ACE2 (P = 0.006) mRNA were also seen in the viable myocardium of MI rats compared with myocardium of control rats. ACE2 protein localized to macrophages, vascular endothelium, smooth muscle, and myocytes. Ramipril attenuated cardiac hypertrophy and inhibited cardiac ACE. In contrast, ramipril had no effect on cardiac ACE2 mRNA, which remained elevated in all areas of the MI rat heart. Immunoreactivity of both ACE and ACE2 increased in failing human hearts. CONCLUSION: The increase in ACE2 after MI suggests that it plays an important role in the negative modulation of the renin angiotensin system in the generation and degradation of angiotensin peptides after cardiac injury.

Aged↗
PubMed2005

Lipids and diabetic renal disease.

Diabetic nephropathy is commonly associated with dyslipidemia, but the role of lipids in the progression of this disorder remains unresolved. In particular, the role of lipid-lowering drugs, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and fibrates, as renoprotective agents is not clarified. Experimental studies have demonstrated that dietary lipids promote renal injury and that statins, independent of their lipid-lowering effects, confer renoprotection via effects on intrarenal hemodynamics and renal cytokine and chemokine expression. Clinical studies have in general been underpowered, but a recent meta-analysis and findings from the Heart Protection Study suggest that statins may be renoprotective. Nevertheless, with the convincing antiatherosclerotic effects of these agents, including in the setting of diabetes, they should be widely administered in the diabetic population with or at risk for nephropathy.

Animals↗
PubMed2005

Advanced-glycation end products in insulin-resistant states.

Insulin resistance is a central component of a number of clinical conditions, including the metabolic syndrome, diabetes, and hypertension. There is emerging evidence that the consequent hyperinsulinemia and visceral adiposity may be directly responsible for the excess cardiovascular morbidity and mortality seen in these conditions. Advanced-glycation end products, a chemically diverse group of compounds found in higher levels in insulin-resistant states, have also been shown to adversely affect endothelial function as well as activate numerous intracellular signaling pathways implicated in the atherosclerotic pathway. In this review, we summarize the factors thought to be important in both the initiation and exacerbation of the insulin-resistant state, and directly examine the potential role of advanced-glycation end products in this process.

Adipose Tissue↗
PubMed2005

Rationale--Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) have a high burden of mortality and cardiovascular morbidity. Additional strategies to modulate cardiovascular risk in this population are needed. Data suggest that anemia is a potent and potentially modifiable risk factor for cardiovascular disease in patients with CKD, but these data remain unsubstantiated by any randomized controlled trial (RCT). Furthermore, the clinical practice guidelines for anemia management in patients with CKD are based on limited data. The need for new RCTs to address critical knowledge deficits, particularly with regard to the impact of anemia therapy on cardiovascular disease and survival, is recognized within the guidelines and independent comprehensive reviews of the existing published trial data. STUDY DESIGN: The Trial to Reduce Cardiovascular Events with Aranesp (Amgen Inc, Thousand Oaks, Calif) (darbepoetin alfa) Therapy (TREAT) is a 4000-patient, multicenter, double-blind RCT, designed to determine the impact of anemia therapy with darbepoetin alfa on mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes mellitus. Subjects will be randomized in a 1:1 manner to either darbepoetin alfa therapy to a target hemoglobin (Hb) of 13 g/dL or control, consisting of placebo for Hb > or =9 g/dL or darbepoetin alfa for Hb <9 g/dL until Hb is again Hb > or =9 g/dL. TREAT is event-driven and has a composite primary end point comprising time to mortality and nonfatal cardiovascular events, including myocardial infarction, myocardial ischemia, stroke, and heart failure. TREAT will provide data that are critical to evolution of the management of cardiovascular risk in this high-risk population.

Anemia↗
PubMed2005

Temporal renal expression of angiogenic growth factors and their receptors in experimental diabetes: role of the renin-angiotensin system.

OBJECTIVE: It has been postulated that vascular endothelial growth factor (VEGF) plays a role in the progression of renal injury. However, the role of other angiogenic factors and their receptors, such as the angiopoietins and Tie2, and in particular their relation to renoprotective therapies, such as agents that interrupt the renin-angiotensin system, have not been studied in the context of diabetes-related renal injury. DESIGN AND METHODS: Renal expression of VEGF, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and their receptors, VEGF-R2 and Tie-2, were assessed using reverse transcription-polymerase chain reaction, immunohistochemistry and Western blotting, in control and streptozotocin diabetic rats, untreated or receiving the AT1 receptor antagonist, valsartan, or the AT2 receptor antagonist, PD123319. RESULTS: Diabetes was associated with increased gene and protein expression of VEGF, VEGF-R2, Ang-1, Ang-2 and Tie-2. AT1 receptor antagonism attenuated gene expression of these cytokines and receptors, yet PD123319, which had no effect on blood pressure, reduced VEGF-R2 and Ang-1 gene expression and decreased VEGF, Ang-1 and Ang-2 protein levels. CONCLUSIONS: In experimental diabetes, there is significant upregulation within the kidney of various angiogenic cytokines and their receptors. Furthermore, the effects of angiotensin II receptor blockade on these parameters is consistent with the VEGF-VEGF-R2 and angiopoietin-Tie-2 axes being modulated in the kidney by haemodynamic factors in the diabetic context.

Angiopoietin-1↗
PubMed2005

Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes.

Recent trials have suggested that inhibitors of the renin-angiotensin system (RAS), such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), may reduce the incidence of new-onset diabetes in patients with or without hypertension and at high risk of developing diabetes. In this review, we critically evaluate the evidence from recent clinical trials for such a potential preventive effect of ACE inhibitors and ARBs, including a meta-analysis of these recent trials. The reduced incidence of diabetes in patients at high risk of developing diabetes by ACE inhibitors or ARBs has been explained by haemodynamic effects, such as improved delivery of insulin and glucose to the peripheral skeletal muscle, and non-haemodynamic effects, including direct effects on glucose transport and insulin signalling pathways, all of which decrease insulin resistance. There is now evidence that the pancreas may contain an in situ active RAS, which appears to be upregulated in an animal model of type 2 diabetes. Thus, ACE inhibitors and ARBs may act by attenuating the deleterious effect of angiotensin II on vasoconstriction, fibrosis, inflammation, apoptosis and beta-cell death in the pancreas, thereby protecting a critical beta-cell mass essential for insulin production. New evidence is presented that ACE inhibitors and ARBs may delay or prevent the development of insulin resistance and diabetes, for which novel mechanisms are suggested. The actions of agents that interrupt the RAS on insulin resistance, obesity and diabetes warrant further investigation in other animal models. Prospective clinical studies with the primary endpoint of the prevention of diabetes are now indicated to (i) further explore whether the inhibitors of the RAS are superior compared to other antihypertensive agents such as calcium channel blockers (CCBs) and (ii) to evaluate the potential beneficial effects of combination antihypertensive regimens on the development of diabetes.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Anti-atherosclerotic and renoprotective effects of combined angiotensin-converting enzyme and neutral endopeptidase inhibition in diabetic apolipoprotein E-knockout mice.

OBJECTIVE: To investigate the effects of the combined angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor omapatrilat on atherosclerosis and renal injury in a model of diabetes-associated accelerated atherosclerosis and renal injury. DESIGN: The study was performed using diabetic apolipoprotein E-knockout (apo E-KO) mice, a model combining hyperlipidemia and hyperglycemia, which leads to accelerated atherosclerosis and renal injury. METHODS: Diabetes was induced by the injection of streptozotocin in 6-week old apo E-KO mice. Diabetic animals received no treatment (n = 12) or treatment with the ACE/NEP inhibitor omapatrilat (30 mg/kg per day, via gavage, n = 12) or quinapril (10 mg/kg per day, in drinking water, n = 12) for 20 weeks. Non-diabetic apo E-KO mice (n = 12) served as controls. RESULTS: Omapatrilat reduced atherosclerosis and protected the mice from renal structural injury and albuminuria. The protective effects were associated with tissue inhibition of aortic and renal ACE and NEP as well as a significant reduction in blood pressure. Omapatrilat had similar anti-atherosclerotic effects compared with the ACE inhibitor quinapril in association with an almost complete inhibition of aortic ACE activity by both drugs. Omapatrilat conferred superior renoprotection in the diabetic apo E-KO mouse compared with quinapril in the context of greater renal ACE inhibition by omapatrilat than seen with quinapril, additional renal NEP inhibition and a modestly enhanced antihypertensive response. CONCLUSIONS: These studies demonstrate the anti-atherosclerotic and renoprotective effects of omapatrilat in diabetic apo E-KO mice, a model of accelerated atherosclerosis and renal injury. These effects were observed in association with the local inhibition of ACE and NEP at the tissue level in the aorta and kidney. These results suggest that the anti-atherosclerotic effect conferred by omapatrilat treatment in the diabetic apo E-KO mouse is predominantly mediated by its capacity to inhibit local vascular ACE. By contrast, in the kidney, local renal ACE and NEP inhibition and the superior antihypertensive effect of omapatrilat all contribute to the renoprotective effect conferred by omapatrilat treatment in the diabetic apo E-KO mouse.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Heparanase inhibition reduces proteinuria in a model of accelerated anti-glomerular basement membrane antibody disease.

BACKGROUND: The beta-d-endoglycosidase, heparanase, is emerging as an important contributor to the pathogenesis of proteinuria. The purpose of the present study therefore was to examine the role of heparanase in a model of accelerated anti-glomerular basement disease (anti-GBM). METHODS: Accelerated anti-GBM disease was induced and animals sacrificed at day 10 to establish heparanase expression using immunohistochemistry and western blot analysis. In addition, cortex was isolated from normal and diseased glomeruli to determine if mRNA levels altered with disease. A previously validated anti-heparanase antibody associated with proteinuria reduction, in a model of membranous nephropathy, was administered prior to disease induction to establish its impact on protein excretion in this model. RESULTS: At day 10 of anti-GBM disease, an increase in glomerular heparanase was shown using immunohistochemistry. Sequential staining studies revealed that this increase was associated with glomerular endothelial, epithelial cells and invading ED-1-positive inflammatory cells. RT-PCR revealed an insignificant 1.2-fold induction of mRNA at day 10 of disease. Western blot analysis of kidney cortex confirmed that the active 58-kDa heparanase species was restricted to diseased kidney at day 10. The inactive 65-kDa precursor, however, was found only in cortex derived from normal kidney. Proteinuria at day 10 of disease was significantly reduced, in the absence of altered rat anti-sheep antibody titres, after administration of a validated polyclonal anti-heparanase antibody (P < 0.05). Furthermore, sheep IgG deposition was not altered by administration of the anti-heparanase antibody. CONCLUSION: These data suggest that heparanase contributes to the pathogenesis of proteinuria in a model of anti-GBM disease.

Animals↗
PubMed2005

Increased tubular organic ion clearance following chronic ACE inhibition in patients with type 1 diabetes.

BACKGROUND: The tubular excretion of creatinine significantly contributes to its clearance. Administration of an angtiotensin-converting enzyme (ACE) inhibitor is associated with increased organic ion clearance in experimental diabetes. This study examines the effect and implications of chronic ACE inhibition on renal organic ion excretion in patients with type 1 diabetes. METHODS: Samples were obtained from the Melbourne Diabetic Nephropathy Study Group (MDNSG) that randomized patients to receive perindopril (N= 11), nifedipine (N= 11), or placebo (N= 8). Albumin excretion rate, creatinine clearance, and isotopic glomerular filtration rate (GFR) were assessed at baseline and after 24 months. In addition, the clearance of the endogenous cations N-methylynicotinamide (NMN), creatinine, and the anion hippurate were determined by high-performance liquid chromatography (HPLC). RESULTS: Following treatment with the ACE inhibitor, perindopril, renal clearance of NMN was increased (+96%) (P < 0.05). There was no difference in patients treated with nifedipine (P= 0.25) and NMN clearance fell in the placebo-treated patients (-26%) (P < 0.05). Changes in NMN clearance were unaffected after adjusting for the effects of perindopril on GFR. However, they were attenuated after adjusting for hippurate clearance, a marker of renal blood flow. This effect of perindopril on NMN clearance was seen in both men and women, regardless of baseline clearance and was correlated with reduced albuminuria following perindopril treatment. CONCLUSION: Organic ion clearance is increased in patients with diabetes following chronic ACE inhibition. This is consistent with experimental models showing increased ion transporter expression and improved tubular blood flow, following blockade of the renin-angiotensin system (RAS). These findings may have implications for the interpretation of creatinine-based indices in patients with diabetes.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Localization of the ezrin binding epitope for glycated proteins.

ERM proteins (ezrin, radixin, and moesin) have recently been identified as a new class of AGE-binding proteins. ERM proteins link the plasma membrane with the actin cytoskeleton and regulate cell shape, motility, adhesion, and signal transduction. ERM proteins have three structural domains: the N-terminal domain, a coiled midregion, and the C-terminal domain. The N-terminal domain binds to a number of plasma membrane ligands and is involved in signal transduction, while the C-domain binds to actin filaments. Binding studies with isolated structural domains showed that glycated proteins bind to an epitope within the N-terminal domain of ezrin (aa 1-324). It is postulated that some of the cellular effects of AGEs leading to diabetic complications may be mediated by binding to this region of ezrin, thereby interrupting the cross-linking between the plasma membrane and actin cytoskeleton and downstream signaling pathways. Indeed, changes in actin arrangement, cell shape, and adhesion have been described in diabetes, and AGE-BSA inhibits ezrin-dependent tubulogenesis of LLC-PK1 proximal tubular cells. For future development of antagonists, further identification of the ezrin-binding epitope for glycated proteins is required.

Animals↗
PubMed2005

Low-molecular weight advanced glycation end products: markers of tissue AGE accumulation and more?

Incomplete digestion of advanced glycation end product (AGE)-modified protein results in the formation of low-molecular weight degradation products incorporating AGE modifications (LMW-AGEs). In addition to being biomarkers of AGE modification, LMW-AGEs may have a high toxic potential, being free to interact with AGE receptors at distant sites via the circulation. Several free AGEs have been identified, including pentosidine, N(epsilon)-(carboxymethyl)lysine (CML), and free-imidazole AGEs. In addition, fluorescence (370 nm [excitation]/440 nm [emission]) in the LMW phase of serum correlates with tissue fluorescence, an established marker for AGE modification. In experimental diabetes, LMW fluorescence increases with duration of disease and is normalized with the AGE inhibitor aminoguanidine. LMW fluorescence is also higher in patients with diabetes, in whom it is associated with glomerular filtration rate and hemoglobin. Patients with hyperfiltration have lower LMW fluorescence than those with normal renal function, which may protect them from AGE accumulation in the short term. These findings provide clinical support for the association between AGEs and progressive renal injury in diabetes.

Biomarkers↗
PubMed2005

Can advanced glycation end product inhibitors modulate more than one pathway to enhance renoprotection in diabetes?

Although advanced glycation end products (AGEs) have been postulated to contribute to diabetic nephropathy in their own right, advanced glycation is clearly only one pathway by which renal injury may be induced in diabetes. The interaction between metabolic and hemodynamic factors amplifies the deleterious effects of the diabetic milieu, thereby reducing the threshold for microvascular injury via common mechanisms. This includes interactions between AGE-mediated pathways and the renin angiotensin system, oxidative stress, protein kinase C, and growth factors, which play a significant role in the development and progression of diabetic renal disease. As it is likely that the future of preventive therapy will not involve a single "cure-all" agent, it seems that a highly relevant question in diabetic nephropathy should be, which pathogenic pathways are already addressed by currently available therapies? Combination therapies that target multiple pathways may ultimately be more successful than those that modify a single pathway. Therefore, research into synergistic interactions among the various pathogenic pathways leading to diabetic complications is critical in order to develop interventions that confer optimal end-organ protection.

Animals↗
PubMed2005

Effects of advanced glycation end products on ezrin-dependent functions in LLC-PK1 proximal tubule cells.

We have recently shown that advanced glycation products (AGEs) bind to the ERM (ezrin, radixin, moesin) family of proteins. ERM proteins act as cross-linkers between cell membrane proteins and the actin cytoskeleton. They are also involved in signal transduction pathways. They therefore have a critical role in normal cell processes, including modulation of cell shape, adhesion, and motility. We postulate that AGEs may contribute to diabetic complications by disrupting ERM function. In support of this hypothesis, AGEs inhibit ezrin-dependent tubulogenesis of proximal tubule cells. Phosphorylation is an important activating mechanism for ERM proteins, and AGEs inhibit ezrin phosphorylation mediated by the epidermal growth factor receptor.

Animals↗
PubMed2005

Agents in development for the treatment of diabetic nephropathy.

Diabetic nephropathy is a leading cause of end-stage renal disease, and accounts for significant morbidity and mortality in patients with diabetes. Diabetic nephropathy seems to occur as a result of an interaction between metabolic and haemodynamic factors, which activate common pathways that lead to renal damage. In the past, the treatment of diabetic nephropathy has focused on the control of hyperglycaemia. Newer targets, some of which are linked to glucose-dependent pathways, appear to be a major focus of new treatments directed against the development and progression of renal damage as a result of diabetes. It is anticipated that additional therapeutic approaches that inhibit both metabolic and haemodynamic pathways will include strategies that target growth factors, cytokines and intracellular second messengers. Such an approach is expected to lead to improved therapies for the treatment of diabetic nephropathy.

Clinical Trials as Topic↗