RESUMO
High-fat diet (HFD)-induced obesity is a cause of resistant hypertension. We have shown a possible link between histone deacetylases (HDACs) and renal angiotensinogen (Agt) upregulation in the HFD-induced hypertension, whereas the underlying mechanisms remain to be elucidated. Here, using a HDAC1/2 inhibitor romidepsin (FK228) and siRNAs, we determined roles of HDAC1 and HDAC2 in HFD-induced hypertension and found the pathologic signaling axis between HDAC1 and Agt transcription. Treatment with FK228 canceled the increased blood pressure of male C57BL/6 mice induced by HFD. FK228 also blocked upregulation of renal Agt mRNA, protein, angiotensin II (Ang II) or serum Ang II. Activation and nuclear accumulation of both HDAC1 and HDAC2 occurred in the HFD group. The HFD-induced HDAC activation was associated with an increase in deacetylated c-Myc transcription factor. Silencing of HDAC1, HDAC2 or c-Myc in HRPTEpi cells decreased Agt expression. However, only HDAC1 knockdown, but not HDAC2, increased c-Myc acetylation, suggesting selective roles in two enzymes. Chromatin immunoprecipitation assay revealed that HFD induced the binding of HDAC1 and deacetylated c-Myc at the Agt gene promoter. A putative c-Myc binding sequence in the promotor region was necessary for Agt transcription. Inhibition of c-Myc downregulated Agt and Ang II levels in kidney and serum, ameliorating HFD-induced hypertension. Thus, the abnormal HDAC1/2 in the kidney may be responsible for the upregulation of the Agt gene expression and hypertension. The results expose the pathologic HDAC1/c-myc signaling axis in kidney as a promising therapeutic target for obesity-associated resistant hypertension.
Assuntos
Angiotensinogênio , Hipertensão , Animais , Masculino , Camundongos , Angiotensina II/metabolismo , Angiotensinogênio/genética , Dieta Hiperlipídica/efeitos adversos , Hipertensão/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de SinaisRESUMO
Solid-state molecular phonons play a crucial role in the performance of diverse photonic and optoelectronic devices. In this work, new organic terahertz (THz) generators based on a catechol group that acts as a phonon suppressing intermolecular adhesive are developed. The catechol group is widely used in mussel-inspired mechanical adhesive chemistry. Newly designed organic electro-optic crystals consist of catechol-based nonlinear optical 4-(3,4-dihydroxystyryl)-1-methylpyridinium (DHP) cations and 4-(trifluoromethyl)benzenesulfonate anions (TFS), which both have multiple interionic interaction capability. Interestingly, compared to benchmark organic crystals for THz generators, DHP-TFS crystals concomitantly achieve top level values of the lowest void volume and the highest crystal density, resulting in an exceptionally small amplitude of solid-state molecular phonons. Simultaneously achieving small molecular phonon amplitude, large optical nonlinearity and good phase matching at infrared optical pump wavelengths, DHP-TFS crystals are capable of generating broadband THz waves of up to 16 THz with high optical-to-THz conversion efficiency; one order of magnitude higher than commercial inorganic THz generators.
RESUMO
[Figure: see text].
Assuntos
Dieta Hiperlipídica , Inibidores de Histona Desacetilases/farmacologia , Sulfeto de Hidrogênio/metabolismo , Ácidos Hidroxâmicos/farmacologia , Hipertensão/tratamento farmacológico , Metionina Sulfóxido Redutases/fisiologia , Naftalenos/farmacologia , Animais , Inibidores de Histona Desacetilases/uso terapêutico , Histonas/metabolismo , Hipertensão/etiologia , Masculino , Metionina Sulfóxido Redutases/genética , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Regiões Promotoras Genéticas , VasoconstriçãoRESUMO
Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) produces NADPH, which is known to inhibit mitochondrial oxidative stress. Ureteral obstruction induces kidney inflammation and fibrosis via oxidative stress. Here, we investigated the role and underlying mechanism of IDH2 in unilateral ureteral obstruction (UUO)-induced kidney inflammation using IDH2 gene deleted mice (IDH2-/-). Eight- to 10-week-old female IDH2-/- mice and wild type (IDH2+/+) littermates were subjected to UUO and kidneys were harvested 5 days after UUO. IDH2 was not detected in the kidneys of IDH2-/- mice, while UUO decreased IDH2 in IDH2+/+ mice. UUO increased the expressions of markers of oxidative stress in both IDH2+/+ and IDH2-/- mice, and these changes were greater in IDH2-/- mice compared to IDH2+/+ mice. Bone marrow-derived macrophages of IDH2-/- mice showed a more migrating phenotype with greater ruffle formation and Rac1 distribution than that of IDH2+/+ mice. Correspondently, UUO-induced infiltration of monocytes/macrophages was greater in IDH2-/- mice compared to IDH2+/+ mice. Taken together, these data demonstrate that IDH2 plays a protective role against UUO-induced inflammation through inhibition of oxidative stress and macrophage infiltration.
RESUMO
Obesity is growing rapidly worldwide due to consumption of westernized diet and lack of exercise. Obesity is one of the major risk factors of hypertension. The novel histone deacetylase (HDAC) inhibitor CG200745 was originally developed to treat various cancers. Previous studies showed that CG200745 attenuated hypertension through inhibition of cardiac hypertrophy and fibrosis in deoxycorticosterone acetate-induced hypertensive rat. The purpose of this study is to investigate the role and underlying mechanism of CG200745 in high-fat diet (HFD)-induced hypertension. Nine-week old C57BL/6 mice were fed a normal diet (ND) or HFD for 17 weeks. Each group of mice was treated with vehicle or CG200745 by intraperitoneal injection for 9 days. HFD group showed higher body weight, blood pressure (BP), HDAC activities, angiotensinogen and renin expressions in kidney, angiotensin-converting enzyme (ACE) expression in the lung, serum angiotensin II (Ang II) concentration, and myosin light chain20 (MLC20) phosphorylation in mesenteric artery compared with ND group. CG200745 lowered BP, HDAC activity, renin and angiotensinogen in the kidney, ACE in the lung, serum Ang II level, and phosphorylation of MLC20 in HFD group. In conclusion, CG200745 ameliorated HFD-induced hypertension through inhibition of HDAC/Ang II/vascular contraction axis. Our results offer CG200745 as a novel therapeutic option for HFD-induced hypertension.