azilsartan and Inflammation

Hypertension is a major risk factor for cardiovascular disease (CVD) and is associated with increased bone loss due to excessive activity of the local renin-angiotensin system (RAS). Angiotensinogen/Angiotensin (ANG) II/Angiotensin II type 1 receptor (AT1R) axis is considered as the core axis regulating RAS activity. Azilsartan is an FDA-approved selective AT1R antagonist that is used to treat hypertension. This study aimed to determine whether azilsartan affects formation of osteoclast, resorption of bone, and the expression of cytokines linked with osteoclastogenesis during lipopolysaccharide (LPS)-triggered inflammation. Azilsartan-treated calvariae exhibited significantly lower bone resorption and osteoclastogenesis than those treated with LPS alone.. These findings imply that azilsartan prevents LPS-triggered TNF-α production in macrophages, which in turn prevents LPS-Triggered osteoclast formation and bone resorption

Topics: Animals; Bone Resorption; Hypertension; Inflammation; Lipopolysaccharides; Macrophages; Mice; Mitogen-Activated Protein Kinases; Osteogenesis; RNA, Messenger; Tumor Necrosis Factor-alpha

Atherosclerosis is a common cardiovascular disease with high morbidity and mortality. It is reported to be related to oscillatory shear stress (OSS)-induced endothelial dysfunction and excessive production of inflammatory factors. Azilsartan, a specific antagonist of the angiotensin II receptor, has been approved for the management of hypertensive subjects with diabetes mellitus type II (DMII). The present study will investigate the effects of azilsartan against OSS-induced endothelial dysfunction and inflammation, as well as the underlying mechanism.. Cell viability was detected using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay were used to determine the expression levels of IL-6, TNF-α, IL-1β, VCAM-1, and ICAM-1 in human aortic endothelial cells (HAECs). Generation of reactive oxygen species (ROS) was measured using 2'-7'dichlorofluorescin diacetate (DCFH-DA) staining, and the level of reduced glutathione (GSH) was evaluated using a commercial kit. The adhesion of THP-1 monocytes to HAECs was evaluated using calcein-AM staining. The expression level of KLF6 was determined using qRT-PCR and Western blot analysis.. According to the result of the MTT assay, 5 and 10 μM azilsartan were considered as the optimized concentrations applied in the present study. The elevated production of IL-6, TNF-α, and IL-1β, increased levels of ROS, decreased levels of reduced GSH, upregulated VCAM-1, ICAM-1, and E-selectin, and the aggravated adhesion of THP-1 cells to HAECs induced by OSS were all reversed by the introduction of azilsartan. The downregulation of KLF6 induced by OSS was significantly reversed by azilsartan. By knocking down the expression of KLF6, the suppressed adhesion of THP-1 cells to the HAECs, and the downregulation of VCAM-1 and ICAM-1 induced by azilsartan in OSS-stimulated HAECs were greatly reversed.. The protective effects of azilsartan against OSS-induced endothelial dysfunction and inflammation might be mediated by KLF6.

Topics: Benzimidazoles; Endothelial Cells; Humans; Inflammation; Kruppel-Like Factor 6; Oxadiazoles; Stress, Mechanical; THP-1 Cells

Advanced glycation end products (AGEs)-induced inflammation and degradation of aggrecan in human chondrocytes play an important role in the progression and development of osteoarthritis (OA). Azilsartan, an angiotensin II receptor antagonist, has been licensed for the treatment of high blood pressure. However, the effects of Azilsartan in OA and AGEs-induced damages in chondrocytes have not been previously reported. The injured chondrocytes model was established by incubating with 5 μmol/L AGEs. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was used to evaluate the cell viability of treated SW1353 cells. The gene expression levels of interleukin-1α (IL-1α), tumor necrosis factor-β (TNF-β), IL-6, a disintegrin-like and metallopeptidase with thrombospondin type motif-4 (ADAMTS-4), ADAMTS-5, Aggrecan, and Sox-4 were evaluated using quantitative real-time polymerase chain reaction and their protein levels were determined using enzyme-linked immunosorbent assay or Western blot analysis. Mitogen-activated protein kinase p38 pathway was surveyed using phosp-p38 level and its specific inhibitor SB203580 was employed to block the p38 pathway. The overexpression of Sox4 plasmid was transfected into SW1353 cells to assess its regulation on ADAMTS-4 and ADAMTS-5. Azilsartan reduced AGEs-induced production of proinflammatory cytokines, such as IL-1α, TNF-β, and IL-6. Azilsartan prevented AGEs-induced expressions of ADAMTS-4 and ADAMTS-5 as well as the reduction of aggrecan. Mechanistically, AGEs treatment increased the expression of Sox4 in a dose-dependent manner. AGE treatment increased the level of phosphorylated p38. However, treatment with the p38 inhibitor SB203580 inhibited AGEs-induced expression of Sox4, suggesting that AGEs-induced expression of Sox4 is mediated by p38. Furthermore, Azilsartan suppressed AGEs-induced phosphorylation of p38 and expression of Sox4. Finally, the overexpression of Sox4 abolished the inhibitory effects of Azilsartan against the expressions of ADAMTS-4 and ADAMTS-5. Azilsartan treatment prevented AGEs-induced inflammatory response and degradation of aggrecan through inhibition of Sox4.

Topics: Aggrecans; Benzimidazoles; Cell Line; Chondrocytes; Glycation End Products, Advanced; Humans; Inflammation; Oxadiazoles; Proteolysis; SOXC Transcription Factors

Metabolic syndrome (MetS) and chronic kidney disease are global health issues. Metabolic syndrome induces hypertension and commonly results in renal damage. The optimal therapy for hypertension in MetS is unknown. Thiazide diuretics are first-line therapy; however, these drugs may have untoward effects. In the present study we investigated the effects of azilsartan (AZL), chlorthalidone (CLTD) and their combination on blood pressure and renal injury in a rodent model with features of MetS. Dahl salt-sensitive rats were fed high-fat (36% fat), high-salt (4% NaCl) diet. Groups were then treated with vehicle, AZL (3 mg/kg per day), CLTD (5 mg/kg per day) or AZL + CLTD. Mean arterial pressure was recorded continuously by telemetry. After 26 days, rats were killed humanely and their kidneys were harvested for histology. Both AZL and CLTD attenuated the rise in blood pressure compared with vehicle and the combination further reduced blood pressure compared with CLTD alone. All treatments reduced proteinuria and albuminuria. Nephrinuria was prevented only in groups treated with AZL. Nephrinuria was 57% lower and proteinuria was 47% lower with combination therapy compared with AZL alone. All treatments reduced the number of inflammatory cells in the kidney. In conclusion, in our model, AZL and CLTD lower blood pressure and exhibit renal protective effects. Treatment with AZL offers additional protection, as evidenced by lower nephrinuria and plasma monocyte chemoattractant protein-1 levels. Combination therapy afforded the greatest protective effects and may be the best choice for hypertensive therapy in MetS.

Topics: Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Arterial Pressure; Benzimidazoles; Chlorthalidone; Diet, High-Fat; Drug Therapy, Combination; Inflammation; Kidney; Male; Oxadiazoles; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary