Search

Diabetic kidney disease commonly is associated with an increased risk of cardiovascular disease. There are traditional common risk factors for both conditions including hypertension and poor glycemic control. However, it is likely that there are other pathophysiological mechanisms that explain the clinical phenomenon of increased cardiovascular disease in diabetic patients with chronic kidney and vice versa. Current management of both conditions includes aggressive glucose and blood pressure control. The protective role of treating dyslipidemia has been shown for cardiovascular disease, but the results for renal disease are not as clear. The advent of new classes of glucose-lowering agents such as sodium glucose co-transporter2 inhibitors and glucagon-like peptide-1 agonists has resulted in impressive effects on both cardiovascular and renal disease in diabetes. However, how these drugs act independently of glucose lowering to confer both kidney and cardiovascular protection has not been fully elucidated. Nevertheless, these new treatments provide optimism for reducing both microvascular and macrovascular complications in diabetes, which represent the major causes of morbidity and premature mortality in this condition. [ABSTRACT FROM AUTHOR]

Human NADPH oxidase 5 (NOX5) is expressed and functionally active in peripheral blood mononuclear cells (PBMCs). Increased NOX5 expression has been demonstrated in atherosclerotic plaques of diabetic patients with associated coronary artery disease (CAD) and within diabetic kidney biopsies. We postulate that NOX5 expression in circulating PBMCs is particularly increased in diabetic patients with comorbid unstable CAD and chronic kidney disease (CKD). 64 males aged 33-85 years underwent elective or emergency coronary angiography/angioplasty at the Alfred Hospital Catheter Laboratory. PBMCs from whole blood were processed for flow-cytometry to measure NOX5 protein. In parallel, NOX5 gene expression was measured in PBMCs by qPCR. NOX5 protein expression in PBMCs was primarily driven by expression in monocytes (CD 45+/CD14+ cells) and was increased in diabetic patients with CKD versus without CKD (29.0±3.5 vs 12.8±2.3 AU; p=0.0007). CAD with acute presentation was associated with increased NOX5 expression versus elective presentation (24.7±2.7 vs 16.3±2.0 AU; p=0.013), especially in diabetic patients presenting acutely versus electively (28.2±3.5 vs 15.3±2.9 AU; p=0.0070). NOX5 expression was increased in diabetic patients with both CKD and acute presentation versus non-diabetic patients without CKD presenting electively (36.1±4.3 vs 11.9±3.4 AU; p=0.0003). A 3-fold upregulation of NOX5 gene was observed in diabetic patients with CAD and CKD versus diabetic patients with CAD but without CKD (p=0.044). Unstable CAD and CKD appear to be key factors for increased NOX5 expression in circulating PBMC in patients with clustering diabetic complications. Measurement of NOX5 in PBMCs may serve as a valuable prognostic biomarker and therapeutic target. [ABSTRACT FROM AUTHOR]

Reports on the estimated number of people worldwide who will have diabetes by the year of 2025, according to the World Health Organization. Percentage of newly diagnosed patients with type 2 diabetes; Development of diabetic nephropathy; Total number of people with type 1 diabetes.

Explores the role of lipid-lowering treatment in the subtotal nephrectomy model. Reduction of proteinuria and glomerulosclerosis with atorvastatin therapy; Identification of the renoprotective effects of 3-hydroxy-3-methylglutaryl coenzyme A; Effect of atorvastatin on renal function.

Kidney disease caused by type 1 diabetes can progress to end stage renal disease and can increase mortality risk. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) plays a major role in producing oxidative stress in the kidney in diabetes, and its activity is attenuated by GKT137831, an oral Nox inhibitor with predominant inhibitory action on Nox-1 and Nox − 4. Previous studies have demonstrated renoprotective effects with GKT137831 in various experimental models of type 1 diabetes-related kidney disease. This study will evaluate the effect of GKT137831 in treating clinical diabetic kidney disease. This is a multi-center, randomized, placebo-controlled trial, parallel arm study evaluating the effect on albuminuria of treatment with GKT137831 400 mg BID for 48 weeks. The study will randomize 142 participants who have persistent albuminuria and estimated glomerular filtration rate (eGFR) at baseline of at least 40 ml/min/1.73m2. Difference between arms in urine albumin to creatinine ratio. Secondary outcome measures include eGFR. This study is important because it may identify a new way of slowing renal disease progression in people with type 1 diabetes and albuminuria already receiving standard of care treatment. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) have been mainly viewed as unwanted by-products of cellular metabolism, oxidative stress, a sign of a cellular redox imbalance, and potential disease mechanisms, such as in diabetes mellitus (DM). Antioxidant therapies, however, have failed to provide clinical benefit. This paradox can be explained by recent discoveries that ROS have mainly essential signaling and metabolic functions and evolutionally conserved physiological enzymatic sources. Disease can occur when ROS accumulate in nonphysiological concentrations, locations, or forms. By focusing on disease-relevant sources and targets of ROS, and leaving ROS physiology intact, precise therapeutic interventions are now possible and are entering clinical trials. Their outcomes are likely to profoundly change our concepts of ROS in DM and in medicine in general. Lack of comprehensive understanding of DM and its complications, together with its increasing prevalence, represent a major unmet medical need. There is quite a lot known about its mechanisms, but more is needed. Reactive oxygen species (ROS) may hold the answer to this need, but long-standing misconceptions about oxidative stress and the inefficacy of antioxidants have prevented clinical breakthroughs. A new understanding of ROS as both essential signaling molecules and pathomechanism have led to the identification, at different stages of diabetes, of different therapeutically relevant sources and targets of ROS. Network pharmacology and precision diagnostics, currently in advanced stages of clinical development, in conjunction with essential lifestyle changes, will revolutionize the therapy and prevention of diabetes and its end-organ damage. [ABSTRACT FROM AUTHOR]

Smooth muscle cell (SMC) proliferation and fibrosis contribute to the development of advanced atherosclerotic lesions. Oxidative stress caused by increased production or unphysiological location of reactive oxygen species (ROS) is a known major pathomechanism. However, in atherosclerosis, in particular under hyperglycaemic/diabetic conditions, the hydrogen peroxide-producing NADPH oxidase type 4 (NOX4) is protective. Here we aim to elucidate the mechanisms underlying this paradoxical atheroprotection of vascular smooth muscle NOX4 under conditions of normo- and hyperglycaemia both in vivo and ex vivo . Following 20-weeks of streptozotocin-induced diabetes, Apoe −/− mice showed a reduction in SM-alpha-actin and calponin gene expression with concomitant increases in platelet-derived growth factor (PDGF), osteopontin (OPN) and the extracellular matrix (ECM) protein fibronectin when compared to non-diabetic controls. Genetic deletion of Nox4 ( Nox4 −/ − Apoe −/− ) exacerbated diabetes-induced expression of PDGF, OPN, collagen I, and proliferation marker Ki67. Aortic SMCs isolated from NOX4-deficient mice exhibited a dedifferentiated phenotype including loss of contractile gene expression, increased proliferation and ECM production as well as elevated levels of NOX1-associated ROS. Mechanistic studies revealed that elevated PDGF signalling in NOX4-deficient SMCs mediated the loss of calponin and increase in fibronectin, while the upregulation of NOX1 was associated with the increased expression of OPN and markers of proliferation. These findings demonstrate that NOX4 actively regulates SMC pathophysiological responses in diabetic Apoe −/− mice and in primary mouse SMCs through the activities of PDGF and NOX1. [ABSTRACT FROM AUTHOR]

Objective/Rationale Both the renin-angiotensin system (RAS) and the receptor for advanced glycation end products (RAGE) potentiate diabetes-associated atherosclerosis (DAA). We assessed the effectiveness of concomitant RAS and RAGE inhibition on DAA. Methods Diabetic (5 x 55 mg/kg streptozotocin daily) and non-diabetic male RAGE/apolipoprotein E double knockout (RAGE/apoE DKO) mice were treated with quinapril (30 mg/kg/day) for 20 weeks. At the end of the study aortic plaques were assessed. Results Diabetic RAGE/apoE DKO showed significantly less plaque area than diabetic apoE KO mice. Plaque deposition was almost abolished in quinapril treated diabetic RAGE/apoE DKOs, with significant attenuation of vascular collagen deposition, nitrotyrosine staining, and reduced macrophage infiltration. Expression of the advanced glycation end product receptor 3 (galectin 3) was also significantly reduced. Conclusion Concomitant inhibition of RAS and RAGE signalling almost completely inhibited the development of experimental DAA. A dual therapeutic approach may be a superior strategy for the treatment of diabetic macrovascular disease. [ABSTRACT FROM AUTHOR]

Renal fibrosis results from excessive accumulation of extracellular matrix mainly driven by transforming growth factor-β1 (TGF-β1). Certain microRNAs have been implicated in this disease, and here we examine the role of let-7b. Rat proximal tubular epithelial cells (NRK52E) were treated with TGF-β1 for 3 days to assess the expression of markers of fibrosis and let-7b. These factors were also assessed in two mouse models representing early and more advanced diabetic nephropathy and in the non-diabetic adenine-induced renal fibrosis model. TGF-β1 downregulated the expression of let-7b and induced fibrogenesis in NRK52E cells. Ectopic expression of let-7b repressed TGF-β1 receptor 1 (TGFBR1) expression directly by targeting the two let-7b binding sites in the 3'-untranslated region of that gene, reduced expression of extracellular matrix proteins, decreased SMAD3 activity, and attenuated the profibrotic effects of TGF-β1. Knockdown of let-7b elevated TGFBR1 expression and mimicked some of the profibrotic effects of TGF-β1. Consistent with these observations, let-7b expression was also reduced in models of both diabetic and non-diabetic renal fibrosis with the upregulation of TGFBR1. Thus, let-7b microRNA represents a potential new target for the treatment of renal fibrosis in diabetic and non-diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Abstract: Cardiac oxidative stress is an early event associated with diabetic cardiomyopathy, triggered by hyperglycemia. We tested the hypothesis that targeting left-ventricular (LV) reactive oxygen species (ROS) upregulation subsequent to hyperglycemia attenuates type 1 diabetes-induced LV remodeling and dysfunction, accompanied by attenuated proinflammatory markers and cardiomyocyte apoptosis. Male 6-week-old mice received either streptozotocin (55mg/kg/day for 5 days), to induce type 1 diabetes, or citrate buffer vehicle. After 4 weeks of hyperglycemia, the mice were allocated to coenzyme Q10 supplementation (10mg/kg/day), treatment with the angiotensin-converting-enzyme inhibitor (ACE-I) ramipril (3mg/kg/day), treatment with olive oil vehicle, or no treatment for 8 weeks. Type 1 diabetes upregulated LV NADPH oxidase (Nox2, p22phox, p47phox and superoxide production), LV uncoupling protein UCP3 expression, and both LV and systemic oxidative stress (LV 3-nitrotyrosine and plasma lipid peroxidation). All of these were significantly attenuated by coenzyme Q10. Coenzyme Q10 substantially limited type 1 diabetes-induced impairments in LV diastolic function (E:A ratio and deceleration time by echocardiography, LV end-diastolic pressure, and LV −dP/dt by micromanometry), LV remodeling (cardiomyocyte hypertrophy, cardiac fibrosis, apoptosis), and LV expression of proinflammatory mediators (tumor necrosis factor-α, with a similar trend for interleukin IL-1β). Coenzyme Q10's actions were independent of glycemic control, body mass, and blood pressure. Coenzyme Q10 compared favorably to improvements observed with ramipril. In summary, these data suggest that coenzyme Q10 effectively targets LV ROS upregulation to limit type 1 diabetic cardiomyopathy. Coenzyme Q10 supplementation may thus represent an effective alternative to ACE-Is for the treatment of cardiac complications in type 1 diabetic patients. [Copyright &y& Elsevier]

Abstract: Objective: Recent reports have suggested that dual peroxisome proliferator-activated receptor (PPAR) α/γ agonists are associated with adverse cardiovascular events. This study aimed to investigate the actions of the non-thiazolidinedione PPARα/γ agonist, compound 3q, on plaque development in the apolipoprotein E knockout (apoE KO) mouse, a recognised model of accelerated plaque development. Methods: Six-week-old male apoE KO mice were randomised to receive the dual PPARα/γ agonist, compound 3q (3mg/kg/day), the PPARγ agonist, rosiglitazone (20mg/kg/day), the PPARα agonist, gemfibrozil (100mg/kg/day) by gavage or no treatment for 20 weeks (n =12/group). Results: Gemfibrozil and rosiglitazone significantly reduced lesion area. However, compound 3q was associated with a three-fold increase in total plaque area (versus control p <0.001). This was associated with an upregulation of markers of plaque instability including vascular cell adhesion molecule-1 (3.5-fold, p <0.001), P-selectin (3.4-fold, p <0.001) monocyte chemoattractant protein-1 (3.4-fold; p <0.001) as well as the scavenger receptor, CD36 (2-fold, p <0.01). These disparate effects were observed with the dual PPAR agonist despite lowering LDL cholesterol and improving insulin sensitivity to a similar extent to PPARα and γ agonists used individually. Conclusion: The finding of increased atherogenesis following a dual PPARα/γ agonist is consistent with recent clinical findings. These data provide an important framework for further exploring the potential utility and safety of combinatorial approaches. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]