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Biomedical subjects

Mark E Cooper

Publications and source records attributed to Mark E Cooper.

At least 19 recordsLinked to original sources
PubMed2007

Renal microvascular injury in diabetes: RAGE and redox signaling.

Diabetic nephropathy remains a major cause of morbidity and mortality in the diabetic population and is the leading cause of end-stage renal failure in the Western World. Despite current therapeutics including intensified glycemic control and blood pressure lowering agents, renal disease continues to progress relentlessly in diabetic patients, albeit at a lower rate. It is well recognized that metabolic and hemodynamic factors play a central role in accelerating renal disease in diabetes. However, recent experimental studies have suggested that increased generation of reactive oxygen species (ROS) as a result of the diabetic milieu may play a central role in the progression of diabetic microvascular complications. These ROS appear to be generated primarily from mitochondrial sources and via the enzyme, NADPH oxidase. This review focuses on how ROS play a deleterious role in the diabetic kidney and how they are involved in crosstalk among various signaling pathways, ultimately leading to renal dysfunction and structural injury.

Diabetic Angiopathies↗
PubMed2006

Combination therapy with the advanced glycation end product cross-link breaker, alagebrium, and angiotensin converting enzyme inhibitors in diabetes: synergy or redundancy?

Blockade of advanced glycation end product (AGE) accumulation with alagebrium with concomitant angiotensin converting enzyme inhibition was tested for effects on renal function and on other postulated mediators of diabetic renal disease including the renin-angiotensin system, AGEs, mitochondrial and cytosolic oxidative stress, and intracellular signaling molecules. Sprague Dawley rats were rendered diabetic with streptozocin and followed consecutively for 32 wk with nondiabetic controls. Groups were treated with ramipril (1 mg/kg.d; wk 0-32); alagebrium (10 mg/kg.d; wk 16-32); or a combination of both. Although individual treatments had significant effects on albuminuria, no further improvements were seen with combination therapy. Changes in urinary vascular endothelial growth factor excretion mirrored those seen in albuminuria. Diabetes was associated with suppression of circulating angiotensin II in the context of increased circulating and renal levels of the AGE, carboxymethyllysine. All treatments attenuated circulating but not renal carboxymethyllysine levels. The renal gene expression of AGE receptor 1 and soluble receptor for advanced glycation end products were markedly reduced by diabetes and normalized with alagebrium. Diabetes induced renal mitochondrial oxidative stress, which was reduced with alagebrium. In the cytosol, both therapies were equally effective in reducing reactive oxygen species production. Increases in membranous protein kinase C activity in diabetes were attenuated by all treatments, whereas diabetes-associated increases in nuclear factor-kappaB p65 translocation remained unaltered by any therapy. It is evident that renin-angiotensin system blockade and AGE inhibition have specific effects. However, many of their downstream effects appear to be similar, suggesting that their renoprotective benefits may ultimately involve common pathways and key points of convergence, which could be important targets for new therapies in diabetic nephropathy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

The assessment of kidney function by general practitioners in Australian patients with type 2 diabetes (NEFRON-2).

OBJECTIVE: To examine factors influencing the identification of kidney impairment in patients with type 2 diabetes in Australian primary care. DESIGN, SETTING AND PARTICIPANTS: 348 general practitioner investigators were asked to estimate kidney function and its severity in 10-15 consecutively presenting patients with type 2 diabetes (n = 3893). They were then asked, for each patient, whether they routinely estimated kidney function. No instruction was provided on how kidney function should be estimated or categorised. Data were collected between April and September 2005. MAIN OUTCOME MEASURES: Kidney function estimated by the Cockcroft-Gault equation using clinical and laboratory data provided by the GP; estimates of kidney function made by the GP. RESULTS: In 24% of the patients with type 2 diabetes, their GP routinely estimated kidney function. However, few of these patients had impaired kidney function or risk factors for kidney disease. There was a good statistical correlation between the estimates made by GPs and the data-derived estimates (R2 = 0.72). GPs identified patients with data-derived estimates of kidney function < 60 mL/min in over 83% of cases, with a specificity of 90%. Impaired kidney function was reported by GPs in 34.4% of men and 36.4% of women. These figures were discordant with function categorisation using both GP estimates and data-derived values, overlapping in half of the patients. Despite GPs' ability to assess creatinine clearance, "raw" (unstandardised) serum creatinine levels inappropriately influenced the perception of impairment of kidney function. CONCLUSION: GPs can accurately assess kidney function, without reporting of estimated glomerular filtration rate (eGFR). However, even in patients at increased risk of chronic kidney disease, routine estimates are seldom made. Our findings underline the value of the recent initiative recommending automatic reporting of eGFR in Australia.

Aged↗
PubMed2006

Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease.

Epithelial-to-mesenchymal transition (EMT) of tubular cells contributes to the renal accumulation of matrix protein that is associated with diabetic nephropathy. Both TGF-beta1 and advanced glycation end products (AGE) are able to induce EMT in cell culture. This study examined the role of the prosclerotic growth factor connective tissue growth factor (CTGF) as a downstream mediator of these processes. EMT was assessed by the expression of alpha-smooth muscle actin, vimentin, E-cadherin, and matrix proteins and the induction of a myofibroblastic phenotype. CTGF, delivered in an adenovirus or as recombinant human CTGF (250 ng/ml), was shown to induce a partial EMT. This was not blocked by neutralizing anti-TGF-beta1 antibodies, suggesting that this action was TGF-beta1 independent. NRK-52E cells that were exposed to AGE-modified BSA (AGE-BSA; 40 microM) or TGF-beta1 (10 ng/ml) also underwent EMT. This was associated with the induction of CTGF gene and protein expression. Transfection with siRNA to CTGF was able to attenuate EMT-associated phenotypic changes after treatment with AGE or TGF-beta1. These in vitro effects correlate with the in vivo finding of increased CTGF expression in the diabetic kidney, which co-localizes on the tubular epithelium with sites of EMT. In addition, inhibition of AGE accumulation was able to reduce CTGF expression and attenuate renal fibrosis in experimental diabetes. These findings suggest that CTGF represents an important independent mediator of tubular EMT, downstream of the actions of AGE or TGF-beta1. This interaction is likely to play an important role in progressive diabetic nephropathy and strengthens the rationale to consider CTGF as a potential target for the treatment of diabetic nephropathy.

Animals↗
PubMed2006

The burden of chronic kidney disease in Australian patients with type 2 diabetes (the NEFRON study).

OBJECTIVE: To estimate the frequency of chronic kidney disease (CKD) in a clinic-based sample of patients with type 2 diabetes in the setting of Australian primary care. DESIGN, SETTING AND PARTICIPANTS: Expressions of interest were invited from all registered general practitioners in Australia: 500 GP investigators were randomly selected from each stratum (state and urban versus rural location), proportional to the census population, and asked to recruit and provide data for 10-15 consecutively presenting adults with type 2 diabetes between April and September 2005. MAIN OUTCOME MEASURES: Estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m(2) and evidence of kidney damage on urinalysis (eg, microalbuminuria). RESULTS: 348 GP investigators submitted data for 3893 individuals with type 2 diabetes (52% men; median age, 66 years). Almost one in every four patients consulting their GPs had an eGFR < 60 mL/min/1.73 m(2) (23.1%; 95% CI, 21.8%-24.5%). More than one in three had an elevated urinary albumin-creatinine ratio (ACR) (34.6%; 95% CI, 33.3%-35.9%). There was an overlap of 10.4% of patients with both an eGFR < 60 mL/min/1.73 m(2) and an elevated urinary ACR, meaning that almost one in two patients with type 2 diabetes consulting their GPs (47.1%; 95% CI, 45.8%-48.4%) had CKD. CKD was significantly more common in women, in older people, and in individuals with established macrovascular disease. CONCLUSION: CKD is a common complication of type 2 diabetes, found in about half of all patients with type 2 diabetes consulting their GPs. Efforts to increase the recognition of CKD will lead to improved care, and possibly survival, of patients with type 2 diabetes.

Aged↗
PubMed2006

PPAR-alpha and -gamma agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse.

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma agonists are widely used in diabetes. In addition to their effects on lipid and glucose homeostasis, these agents have been postulated to have independent renoprotective actions. In the current study, we assess the efficacy of the PPAR-alpha agonist, gemfibrozil, the PPAR-gamma agonist rosiglitazone and the non-thiazolidinedione PPAR-alpha/gamma coagonist, compound 3q, on kidney structure and function in streptozotocin-treated apolipoprotein E knockout mice. METHODS: Control and streptozotocin-diabetic mice were randomized to receive rosiglitazone (20 mg/kg/day), gemfibrozil (100 mg/kg/day), or compound 3q (3 mg/kg/day) by gavage, or no treatment for a period of 20 weeks. Renal fibrosis was assessed by standard histology and collagen IV immunohistochemistry. Kidney function was assessed by urinary albumin excretion and creatinine clearance. RESULTS: Diabetes in this model was associated with an increase in glomerulosclerosis, tubulointerstitial fibrosis and increased collagen IV deposition in the glomeruli and tubules. All three agents significantly attenuated glomerulosclerosis, tubulointerstitial expansion and collagen IV deposition. The increase in albuminuria and the decline in kidney function associated with diabetes in this model were also attenuated by each of these agents, with no superiority observed among various treatment groups. These renoprotective effects were observed in the absence of changes in glucose, insulin or lipid levels or a reduction in blood pressure. CONCLUSIONS: Combined with their independent anti-atherosclerotic actions, and their important effects on dyslipidaemia and insulin resistance, PPAR agonists may be useful for the prevention of diabetic complications, including kidney disease, even in type 1 diabetes.

Animals↗
PubMed2006

Renin angiotensin aldosterone system blockade and renal disease in patients with type 2 diabetes: a subanalysis of Japanese patients from the RENAAL study.

BACKGROUND: The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study has previously shown losartan to confer significant benefits to patients with type 2 diabetes and nephropathy. The original study of 1513 patients included 96 Japanese patients; the present study is a post-hoc analysis of the effects of losartan in this Japanese subpopulation. METHODS: This double-blind, randomized study compared losartan (50 to 100 mg once daily) with placebo. The study medication was taken in addition to conventional antihypertensive treatment, and the mean follow-up period for the Japanese patients was 2.8 years. The primary endpoint was the composite of doubling of serum creatinine, endstage renal disease, or death. Secondary endpoints included changes in proteinuria levels. Safety was also evaluated. RESULTS: The primary composite endpoint was reached in fewer Japanese patients receiving losartan than placebo (50.0% versus 65.4%, respectively). The treatment effects of losartan were more robust when data were corrected for differences in proteinuria at baseline--a significant relative risk reduction of 45% with losartan (P=0.0397) was apparent. Treatment benefit exceeded that attributable to blood pressure changes alone. Levels of proteinuria were reduced with losartan compared with placebo, with an overall losartan treatment effect of 37.8% (P<0.001). Overall, losartan was similarly well tolerated in both the Japanese patients and the total population. CONCLUSIONS: In Japanese patients with type 2 diabetes and nephropathy, losartan offers renal protection and is generally well tolerated.

Adult↗
PubMed2006

Hypertension and diabetes: role of the renin-angiotensin system.

Hypertension is often associated clinically with diabetes as part of the insulin-resistance syndrome or as a manifestation of renal disease. Elevated systemic blood pressure accelerates micro- and macrovascular complications in diabetes. Vasoactive hormone pathways including the renin-angiotensin-aldosterone system (RAAS) appear to play a pivotal role in the pathogenesis and progression of diabetic complications and possible diabetes itself. Recent studies have increased our understanding of the complexity of the RAAS with identification of new components of this cascade including angiotensin-converting enzyme 2 and a putative renin receptor. Agents that interrupt the RAAS confer end-organ protection in diabetes via hemodynamic and non-hemodynamic mechanisms. Trials are investigating the possible role of RAAS blockade in the prevention of type 2 diabetes.

Aldosterone↗
PubMed2006

Preventing diabetes in patients with hypertension: one more reason to block the renin-angiotensin system.

Patients with essential hypertension are at increased risk of type 2 (non-insulin-dependent) diabetes. Recent large studies have been unable to delineate any superiority in one class of antihypertensive drug over another, independent of their effects in reducing blood pressure; however, in the longer term, antihypertensive agents that are able to reduce the risk of diabetes may have a theoretical advantage. To this end, the findings of several recent clinical trials have suggested that blockade of the renin-angiotensin system (RAS) may protect against the development of de-novo diabetes in 'at risk' patients. This beneficial effect appears to outweigh both the adverse metabolic effects of agents used in the control arm of these studies and the control of blood pressure achieved. Furthermore, recent evidence suggests that the RAS may have a direct role in the pathogenesis of diabetes. Angiotensin-mediated increases in oxidative stress, inflammation, and free fatty acids concentrations potentially contribute to beta-cell dysfunction in diabetes. In addition, activation of the RAS 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 RAS with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists also results in the improvement of islet structure and function. At least three large controlled trials are currently under way to study the utility of blockade of the RAS in the development of diabetes, including studies of combination therapy. It is hoped that these studies will demonstrate the true potential of blockade of the RAS for the prevention of diabetes.

Apoptosis↗
PubMed2006

Efficacy and safety of angiotensin II receptor blockade in elderly patients with diabetes.

OBJECTIVE: While national guidelines recommend ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy in patients with diabetes and nephropathy, guidelines concerning elderly patients with diabetes have not endorsed these drugs. We sought to assess the nephroprotective efficacy and safety of ARB therapy in elderly patients by conducting age-specific subgroup analyses using data from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. RESEARCH DESIGN AND METHODS: We studied 1,513 patients with type 2 diabetes and nephropathy who randomly received either losartan or placebo. We tested for effect modification by age of the effect of losartan on the incidence of the predefined end points (doubling of serum creatinine, end-stage renal disease [ESRD], or death) and the risk of adverse events. RESULTS: Of 1,513 participants, 421 (27.8%) were aged >65 years (maximum age 74 years). Age did not modify the efficacy of losartan in reducing the risk of the primary outcome, a composite of doubling of serum creatinine, ESRD, or death (P(interaction) = 0.66) or its individual components (all P(interaction) > 0.44). In patients aged >65 years, losartan reduced the risk of ESRD by 50% (95% CI 30-81, P = 0.005). We found no evidence that older patients were more likely to experience adverse events from losartan such as a rise in serum creatinine or hyperkalemia than younger patients. CONCLUSIONS: Elderly patients had the same level of benefits and risks as younger patients from treatment with losartan. Underuse of ACEI and ARB therapy in elderly patients because of the perceived lack of efficacy or a greater risk of adverse events appears unjustified.

Aged↗
PubMed2006

Serum lipids and the progression of nephropathy in type 1 diabetes.

OBJECTIVE: Dyslipidemia contributes to the progression of microvascular disease in diabetes. However, different lipid variables may be important at different stages of nephropathy. This study examines the pattern of dyslipidemia associated with the progression of nephropathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 152 patients with type 1 diabetes were recruited in order to represent various phases of nephropathy. Patients were followed for 8-9 years, during which time they received standard care. Renal progression was defined a priori as a doubling in albumin excretion (in patients with normo- or microalbuminuria) or a decline in creatinine clearance (in those with macroalbuminuria). A panel of lipid variables was determined and correlated with indexes of progression. RESULTS: In patients with normoalbuminuria (n = 66), progression was associated with male sex (P < 0.05), borderline albuminuria (P = 0.02), and LDL-free cholesterol (P = 0.02). In patients with microalbuminuria (n = 51), progression was independently associated with triglyceride content of VLDL and intermediate-density lipoprotein (both P < 0.05). In patients with macroalbuminuria (n = 36), a significant decline in the renal function (>3 ml x min(-1) x year(-1)) was independently associated with poor glycemic control, hypertension, and LDL size (P < 0.05). When all patients with progressive nephropathy were analyzed together, only LDL cholesterol was predictive on multivariate analysis (P < 0.05), which masked the importance of triglyceride enrichment in microalbuminuria. CONCLUSIONS: Lipid variables are associated with progression of diabetic kidney disease, but the relationship is not the same at all stages. This finding has implications for the design of renoprotective strategies and the interpretation of clinical trials in type 1 diabetes.

Adult↗
PubMed2005

Advanced glycation end products inhibit tubulogenesis and migration of kidney epithelial cells in an ezrin-dependent manner.

Nonenzymatic glycation of proteins to form advanced glycation end products (AGE) is implicated in diabetic complications, including nephropathy. It was shown recently that AGE bind to the ERM (ezrin, radixin, and moesin) family of membrane-cytoskeletal linker proteins in renal homogenates. Herein is reported the effects of AGE-BSA on ezrin-dependent LLC-PK1 kidney epithelial cellular functions: migration and hepatocyte growth factor (HGF)-induced tubulogenesis. LLC-PK1 cells were stably transfected with cDNA for ezrin sense, ezrin antisense, and N-ezrin. Transfection of LLC-PK1 cells with ezrin antisense and dominant negative N-ezrin decreased basal tubulogenesis and migration relative to vector-only transfection, establishing the ezrin dependency of these processes. AGE-BSA (20 or 40 microM) significantly decreased HGF-induced tubulogenesis and basal migration in two vector control lines relative to BSA-treated cells. However, AGE-BSA inhibition of both HGF-induced tubulogenesis and migration was overcome by overexpressing ezrin. These results demonstrate that the AGE-ezrin interaction significantly alters cellular function. These changes may be relevant to detrimental renal consequences as a result of diabetes.

Animals↗
PubMed2005

Interactions between renin angiotensin system and advanced glycation in the kidney.

Although hemodynamic and metabolic factors are individually implicated in the development of diabetic nephropathy, their interaction has not been defined clearly. In this study, the effects of angiotensin II (Ang II) and advanced glycation end products (AGE) both individually on each other are explored and compared. In the first study arm, Sprague-Dawley rats received a continuous infusion of AGE-modified rat serum albumin (RSA) or unmodified RSA for 4 wk with or without the angiotensin receptor type 1 antagonist valsartan. In the second arm, animals received a continuous infusion of Ang II (58.3 ng/kg per min) with or without the AGE inhibitor pyridoxamine. Components of the intrarenal renin-angiotensin system were measured using real time reverse transcription-PCR, immunohistochemistry, and standard angiotensin-converting enzyme (ACE) activity assays. Renal and serum AGE were quantified by immunohistochemistry, ELISA, and AGE-fluorescence. After an infusion of AGE-RSA, renal expression of angiotensinogen, ACE, renin, and angiotensin receptor type 1 were increased significantly (all P < 0.01), and ACE activity was elevated. This was associated with tubular and glomerular hypertrophy and AGE accumulation, which could be antagonized by valsartan. However, valsartan had no effect on increased filtration fraction associated with an AGE-RSA infusion. At the same time, an infusion of Ang II increased the serum and renal accumulation of AGE and advanced oxidation protein products and induced renal hypertrophy and salt retention that could be antagonized by pyridoxamine. However, pyridoxamine had no effect on renal vasoconstriction manifested by reduced renal blood flow. AGE and Ang II have overlapping activities in the kidney. The beneficial effects of blockade of either pathway underline the importance of this interaction in diabetic renal disease and the aging kidney.

Animals↗
PubMed2005

Rosiglitazone attenuates atherosclerosis in a model of insulin insufficiency independent of its metabolic effects.

OBJECTIVE: Recent studies have demonstrated a role for thiazolidinediones in attenuating atherosclerosis. However, these studies were performed in insulin-resistant animal models in association with reductions in insulin and glucose levels. To assess the vascular effects of thiazolidinediones, independent of their metabolic effects, we observed the effect of rosiglitazone on diabetes-associated atherosclerosis in a model of insulin insufficiency. METHODS AND RESULTS: Control and diabetic apolipoprotein E-deficient mice received rosiglitazone or placebo. Diabetic mice demonstrated a 3-fold increase in plaque area, which was attenuated by rosiglitazone. There was no significant difference in glucose, insulin, or cholesterol levels between treated and untreated diabetic animals. Rosiglitazone attenuated the increase in superoxide production observed in diabetic mice. A 4-fold increase in the reverse cholesterol transport marker ABCA1 was observed in treated diabetic mice. Rosiglitazone reduced angiotensin II receptor gene expression in control and diabetic mice, and macrophage accumulation was increased in diabetic mice compared with controls and was attenuated by rosiglitazone. CONCLUSIONS: These findings suggest peroxisome proliferator-activated receptor-gamma ligands such as rosiglitazone confer vascular protection independent of their effects on metabolic control. These antiatherosclerotic effects may have important clinical ramifications not only in insulin resistance/type 2 diabetes and also in type 1 diabetes.

Animals↗