Heterogeneous Effects of Intensive Glycemic and Blood Pressure on Cardiovascular Events Among Diabetes by Living Arrangements.

Background: Although living alone versus with others is a key social element for cardiovascular prevention in diabetes, evidence is lacking about whether the benefit of intensive glycemic and blood pressure (BP) control differs by living arrangements. We thus aim to investigate heterogeneity in the joint effect of intensive glycemic and BP control on cardiovascular events by living arrangements among participants with diabetes.

Methods And Results: This study included 4731 participants with diabetes in the ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes-Blood Pressure) trial.

Exogenous thyroxine increases cardiac GLUT4 translocation in insulin resistant OLETF rats.

During insulin resistance, the heart undergoes a metabolic shift in which fatty acids (FA) account for roughly about 99% of the ATP production. This metabolic shift is indicative of impaired glucose metabolism. A shift in FA metabolism with impaired glucose tolerance can increase reactive oxygen species (ROS), lipotoxicity, and mitochondrial dysfunction, ultimately leading to cardiomyopathy.

The Renin-Angiotensin-Aldosterone System in Metabolic Diseases and Other Pathologies.

It has been our pleasure to have been able to develop two special issues within the International Journal of Molecular Sciences: Renin-Angiotensin-Aldosterone System in Pathologies and Renin-Angiotensin-Aldosterone System in Metabolism & Disease [...

Improved lipogenesis gene expression in liver is associated with elevated plasma angiotensin 1-7 after AT1 receptor blockade in insulin-resistant OLETF rats.

Increased angiotensin II (Ang II) signaling contributes to insulin resistance and liver steatosis. In addition to ameliorating hypertension, angiotensin receptor blockers (ARBs) improve lipid metabolism and hepatic steatosis, which are impaired with metabolic syndrome (MetS). Chronic blockade of the Ang II receptor type 1 (AT1) increases plasma angiotensin 1-7 (Ang 1-7), which mediates mechanisms counterregulatory to AT1 signaling.

N-type calcium channel and renal injury.

Accumulating evidences indicated that voltage-gated calcium channels (VDCC), including L-, T-, N-, and P/Q-type, are present in kidney and contribute to renal injury during various chronic diseases trough different mechanisms. As a voltage-gated calcium channel, N-type calcium channel was firstly been founded predominately distributed on nerve endings which control neurotransmitter releases. Since sympathetic nerve is distributed along renal afferent and efferent arterioles, N-type calcium channel blockade on sympathetic nerve terminals would bring renal dynamic improvement by dilating both arterioles and reducing glomerular pressure.

Chronic AT blockade improves hyperglycemia by decreasing adipocyte inflammation and decreasing hepatic PCK1 and G6PC1 expression in obese rats.

Inappropriate activation of the renin-angiotensin system decreases glucose uptake in peripheral tissues. Chronic angiotensin receptor type 1 (AT) blockade (ARB) increases glucose uptake in skeletal muscle and decreases the abundance of large adipocytes and macrophage infiltration in adipose. However, the contributions of each tissue to the improvement in hyperglycemia in response to AT blockade are not known.

Chronic angiotensin receptor activation promotes hepatic triacylglycerol accumulation during an acute glucose challenge in obese-insulin-resistant OLETF rats.

Purpose: Angiotensin receptor blockers (ARBs) can ameliorate metabolic syndrome (MetS)-associated dyslipidemia, hepatic steatosis, and glucose intolerance, suggesting that angiotensin receptor (AT1) over-activation contributes to impaired lipid and glucose metabolism, which is characteristic of MetS. The aim of this study was to evaluate changes in the lipid profile and proteins of fatty acid uptake, triacylglycerol (TAG) synthesis, and β-oxidation to better understand the links between AT1 overactivation and non-alcoholic fatty liver disease (NAFLD) during MetS.

Methods: Four groups of 25-week-old-rats were used: (1) untreated LETO, (2) untreated OLETF, (3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 weeks) and (4) OLETF ± ARB (MINUS; 10 mg olmesartan/kg/d × 4 weeks, then removed until dissection).

Effects of post-renal anemia treatment with the HIF-PHD inhibitor molidustat on adenine-induced renal anemia and kidney disease in mice.

The kidneys are the major organs for erythropoietin (EPO) production in adults, and thus, kidney damage results in reduced EPO levels and anemia. Inhibitors of Hypoxia-inducible factor-prolyl hydroxylase domain-containing protein (HIF-PHD) are awaited as new therapeutic options for renal anemia. It can be predicted that most patients who receive HIF-PHD inhibitors have renal dysfunction as a cause of anemia.

Simultaneous angiotensin receptor blockade and glucagon-like peptide-1 receptor activation ameliorate albuminuria in obese insulin-resistant rats.

Insulin resistance increases renal oxidant production by upregulating NADPH oxidase 4 (Nox4) expression contributing to oxidative damage and ultimately albuminuria. Inhibition of the renin-angiotensin system (RAS) and activation of glucagon-like peptide-1 (GLP-1) receptor signalling may reverse this effect. However, whether angiotensin receptor type 1 (AT1) blockade and GLP-1 receptor activation improve oxidative damage and albuminuria through different mechanisms is not known.

The p21 dependent G2 arrest of the cell cycle in epithelial tubular cells links to the early stage of renal fibrosis.

Renal fibrosis is accompanied by the progression of chronic kidney disease. Despite a number of past and ongoing studies, our understanding of the underlying mechanisms remains elusive. Here we explored the progression of renal fibrosis using a mouse model of unilateral ureter obstruction.

A mouse model of renal fibrosis to overcome the technical variability in ischaemia/reperfusion injury among operators.

The ischaemia-reperfusion (I/R) model is a widely used model of acute kidney injury (AKI) and renal fibrosis. However, the ischaemia duration that is long enough to cause broad fibrosis shows that a high mortality rate and a short ischaemia duration does not cause fibrosis, resulting in a large variation in fibrosis progression in this experimental model. Inter-operator variation occurs for I/R injury severity because the I/R procedure is complex, which results in poor reproducibility of subsequent fibrosis in the model.

Nrf2-related gene expression is impaired during a glucose challenge in type II diabetic rat hearts.

Diabetic hearts are susceptible to damage from inappropriate activation of the renin angiotensin system (RAS) and hyperglycemic events both of which contribute to increased oxidant production. Prolonged elevation of oxidants impairs mitochondrial enzyme function, further contributing to metabolic derangement. Nuclear factor erythriod-2-related factor 2 (Nrf2) induces antioxidant genes including those for glutathione (GSH) synthesis following translocation to the nucleus.

A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fibrosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice.

Multiple large clinical trials have shown that sodium-glucose cotransporter (SGLT) 2 inhibitors reduce the risk of renal events. However, the mechanism responsible for this outcome remains unknown. Here we investigated the effects of the SGLT2 inhibitor luseogliflozin on the development of renal fibrosis after renal ischemia/reperfusion injury in non-diabetic mice.

Simultaneous GLP-1 receptor activation and angiotensin receptor blockade increase natriuresis independent of altered arterial pressure in obese OLETF rats.

Obesity is associated with an inappropriately activated renin-angiotensin-aldosterone system, suppressed glucagon-like peptide-1 (GLP-1), increased renal Na reabsorption, and hypertension. To assess the link between GLP-1 and angiotensin receptor type 1 (AT) signaling on obesity-associated impairment of urinary Na excretion (UV) and elevated arterial pressure, we measured mean arterial pressure (MAP) and heart rate by radiotelemetry and metabolic parameters for 40 days. We tested the hypothesis that stimulation of GLP-1 signaling provides added benefit to blockade of AT by increasing UV and further reducing arterial pressure in the following groups: (1) untreated Long-Evans Tokushima Otsuka (LETO) rats (n = 7); (2) untreated Otsuka Long-Evans Tokushima Fatty (OLETF) rats (n = 9); (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 9); (4) OLETF + GLP-1 receptor agonist (EXE; 10 µg exenatide/kg/day; n = 7); and (5) OLETF + ARB + EXE (Combo; n = 6).

Angiotensin receptor blockade improves cardiac mitochondrial activity in response to an acute glucose load in obese insulin resistant rats.

Hyperglycemia increases the risk of oxidant overproduction in the heart through activation of a multitude of pathways. Oxidation of mitochondrial enzymes may impair their function resulting in accumulation of intermediates and reverse electron transfer, contributing to mitochondrial dysfunction. Furthermore, the renin-angiotensin system (RAS) becomes inappropriately activated during metabolic syndrome, increasing oxidant production.

Predictive significance of kidney myeloid-related protein 8 expression in patients with obesity- or type 2 diabetes-associated kidney diseases.

Background And Objective: We have reported that toll-like receptor 4 (TLR4) and one of its endogenous ligands, myeloid-related protein 8 (MRP8 or S100A8), play an important role in the progression of diabetic nephropathy in mice. The aim of this study was to evaluate significance of kidney MRP8 expression in patients with obesity- or type 2 diabetes-associated kidney diseases.

Methods: In diabetic, obese or control subjects, MRP8 mRNA and protein expression levels in renal biopsy samples were determined by real-time RT-PCR and immunohistochemistry (n = 28 and 65, respectively), and their associations with baseline and prognostic parameters were analyzed.

Chymase activities and survival in endotoxin-induced human chymase transgenic mice.

We examined the effects of overexpressed human chymase on survival and activity in lipopolysaccharide (LPS)-treated mice. Human chymase transgenic (Tg) and wild-type C57BL/6 (WT) mice were treated with LPS (0.03, 0.

RAS inhibition attenuates cognitive impairment by reducing blood- brain barrier permeability in hypertensive subjects.

Recent studies have suggested that blood-brain barrier (BBB) abnormalities are present from an early stage in patients exhibiting mild symptoms of cognitive impairment during the development of hypertension. There is also growing body of evidence suggesting the potential role of the renin-angiotensin system (RAS) in the pathogenesis of small-vessel disease and cognitive impairment. However, the specific contribution of the RAS to BBB disruption and cognitive impairment remains unclear.

Steroid permeation into the artificial ulcer by combined steroid gel application and balloon dilatation: prevention of esophageal stricture.

Background And Aim: Local steroid injection therapy is effective for preventing esophageal stricture after endoscopic submucosal dissection (ESD) but is associated with the risk of puncture-related complications, such as bleeding. We evaluated the effectiveness of the application of triamcinolone acetonide gel following permeation into a large artificial ESD ulcer by balloon dilatation compared with steroid injection.

Methods: Forty-three patients who underwent ESD for early esophageal cancer approved by the institutional ethics committee and provided consent to participate in this prospective study were divided into two groups using a sealed-envelope randomization method as follows: 23 patients who were treated with local steroid injection and balloon dilatation and 20 patients were treated with steroid application and balloon dilatation.