JTT-654, an 11-beta hydroxysteroid dehydrogenase type 1 inhibitor, improves hypertension and diabetic kidney injury by suppressing angiotensinogen production. | LitMetric
Biological/Pharmacological Research Laboratories, Takatsuki Research Center, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Published: April 2024
AI Article Synopsis
Article Abstract
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays an important role in regulating the expression of glucocorticoid actions in target tissues. Overexpression of 11β-HSD1 in mouse adipose tissue causes a metabolic syndrome-like phenotype, leading to hypertension. Although, many 11β-HSD1 inhibitors have been studied, few have shown a clear ameliorative effect against hypertension. We investigated whether JTT-654, a novel 11β-HSD1 inhibitor, ameliorated hypertension and elucidated the underlying mechanisms. JTT-654 showed inhibitory effects on angiotensinogen production in cortisone-treated 3T3-L1 adipocytes and in a rat model. JTT-654 improved hypertension not only in cortisone-treated rats and spontaneously hypertensive rats (SHR), but also in SHR/NDmcr-cp rats. In the SHR study, JTT-654 and losartan showed the same degree of antihypertensive efficacy. In addition, JTT-654 ameliorated diabetic nephropathy by suppressing renal angiotensinogen production in SHR/NDmcr-cp rats. These effects of JTT-654 were independent of its insulin-sensitizing effects, and similar effects were not observed for pioglitazone, an insulin sensitizer. Moreover, JTT-654 did not affect normotension or hypothalamus-pituitary-adrenal (HPA) axis function in normal Sprague-Dawley rats. Our results indicate that JTT-654 ameliorates hypertension and diabetic nephropathy by inhibiting 11β-HSD1 in the adipose tissue, liver, and kidney.
Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China. Electronic address:
Microglia-mediated neuroinflammation demonstrates a crucial act in the progression of neuropathic pain. Oxidative damage induced by reactive oxygen species (ROS) derived from NADPH oxidase (NOX) in microglia drives proinflammatory microglia activation. Recent evidence points to the central renin angiotensin system (RAS) is involved in oxidative stress and neuroinflammation, with the angiotensin converting enzyme/angiotensin II/angiotensin receptor-1 (ACE/Ang II/AT1R) axis promoting inflammation through increased ROS production, counteracted by the ACE2/Ang (1-7)/Mas receptor (MasR) axis.
Divergent selection of broilers for water conversion ratio has established and high-(HWE) and low- water efficient (LWE) broiler lines. Two 2 × 2 factorial experiments were conducted to assess the gene expression profile of systems involved in renal water homeostasis. In Exp.
* Initial research identified genes linked to blood pressure but had limited success, which has now shifted with advances in gene-editing technologies like CRISPR and RNA-based therapies.
* New treatments targeting the liver to reduce a key protein involved in blood pressure regulation are in clinical trials, showing promising safety and effectiveness, potentially transforming how hypertension is managed.
Metformin, a diabetes medication, appears to offer cardiovascular protection and influences gut microbiota in hypertensive rats.
In the study, metformin treatment increased short-chain fatty acids (SCFAs) in feces, lowered blood pressure, and improved cardiac function, despite some increase in cardiac hypertrophy.
The research suggests that SCFA levels may mediate the observed anti-inflammatory and blood pressure-lowering effects of metformin, even in the absence of diabetes.
Background: Type 2 diabetes mellitus (T2DM) presents a thrombotic environment, contributing to diabetic macroangiopathy and microangiopathy. In this study, the regulation of microthrombosis in T2DM was assessed.
Methods: Platelets from T2DM patients and healthy controls were analyzed using 4D label-free proteomics and bioinformatics.
