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Cells Oct 2022Gut microbiota is the key controller of healthy aging. Hypertension and osteoarthritis (OA) are two frequently co-existing age-related pathologies in older adults. Both...
Gut microbiota is the key controller of healthy aging. Hypertension and osteoarthritis (OA) are two frequently co-existing age-related pathologies in older adults. Both are associated with gut microbiota dysbiosis. Hereby, we explore gut microbiome alteration in the Deoxycorticosterone acetate (DOCA)-induced hypertensive rat model. Captopril, an anti-hypertensive medicine, was chosen to attenuate joint damage. Knee joints were harvested for radiological and histological examination; meanwhile, fecal samples were collected for 16S rRNA and shotgun sequencing. The 16S rRNA data was annotated using Qiime 2 v2019.10, while metagenomic data was functionally profiled with HUMAnN 2.0 database. Differential abundance analyses were adopted to identify the significant bacterial genera and pathways from the gut microbiota. DOCA-induced hypertension induced p16INK4a+ senescent cells (SnCs) accumulation not only in the aorta and kidney ( < 0.05) but also knee joint, which contributed to articular cartilage degradation and subchondral bone disturbance. Captopril removed the p16INK4a + SnCs from different organs, partially lowered blood pressure, and mitigated cartilage damage. Meanwhile, these alterations were found to associate with the reduction of levels in the gut microbiome. As such, gut microbiota dysbiosis might emerge as a metabolic link in chondrocyte senescence induced by DOCA-triggered hypertension. The underlying molecular mechanism warrants further investigation.
Topics: Acetates; Animals; Antihypertensive Agents; Captopril; Chondrocytes; Desoxycorticosterone Acetate; Dysbiosis; Gastrointestinal Microbiome; Hypertension; RNA, Ribosomal, 16S; Rats
PubMed: 36231135
DOI: 10.3390/cells11193173 -
Cardiovascular Research Aug 2021Abundant evidence indicates that oestrogen (E2) plays a protective role against hypertension. Yet, the mechanism underlying the antihypertensive effect of E2 is poorly...
AIMS
Abundant evidence indicates that oestrogen (E2) plays a protective role against hypertension. Yet, the mechanism underlying the antihypertensive effect of E2 is poorly understood. In this study, we sought to determine the mechanism through which E2 inhibits salt-dependent hypertension.
METHODS AND RESULTS
To this end, we performed a series of in vivo and in vitro experiments employing a rat model of hypertension that is produced by deoxycorticosterone acetate (DOCA)-salt treatment after uninephrectomy. We found that E2 prevented DOCA-salt treatment from inducing hypertension, raising plasma arginine-vasopressin (AVP) level, enhancing the depressor effect of the V1a receptor antagonist (Phenylac1,D-Tyr(Et)2,Lys6,Arg8,des-Gly9)-vasopressin, and converting GABAergic inhibition to excitation in hypothalamic magnocellular AVP neurons. Moreover, we obtained results indicating that the E2 modulation of the activity and/or expression of NKCC1 (Cl- importer) and KCC2 (Cl- extruder) underpins the effect of E2 on the transition of GABAergic transmission in AVP neurons. Lastly, we discovered that, in DOCA-salt-treated hypertensive ovariectomized rats, CLP290 (prodrug of the KCC2 activator CLP257, intraperitoneal injections) lowered blood pressure, and plasma AVP level and hyperpolarized GABA equilibrium potential to prevent GABAergic excitation from emerging in the AVP neurons of these animals.
CONCLUSION
Based on these results, we conclude that E2 inhibits salt-dependent hypertension by suppressing GABAergic excitation to decrease the hormonal output of AVP neurons.
Topics: Animals; Antihypertensive Agents; Arginine Vasopressin; Basal Nucleus of Meynert; Blood Pressure; Desoxycorticosterone Acetate; Disease Models, Animal; Estradiol; Female; GABAergic Neurons; Hypertension; Male; Nephrectomy; Ovariectomy; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Solute Carrier Family 12, Member 2; Symporters; Vasoconstriction; Rats
PubMed: 32960965
DOI: 10.1093/cvr/cvaa271 -
Laboratory Investigation; a Journal of... Jan 2023Fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease; however, the mechanisms underlying the effect of...
Fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease; however, the mechanisms underlying the effect of FGF23 on cardiac function remain to be investigated. Herein, we studied the effect of continuous intravenous (CIV) FGF23 loading in a deoxycorticosterone acetate (DOCA)-salt mouse model with mild chronic kidney disease and hypertension as well as heart failure with a preserved ejection fraction. Wild-type male mice were randomly allocated to 4 groups: normal control, vehicle-treated DOCA-salt mice, FGF23-treated DOCA-salt mice, and FGF23- and calcitriol-treated DOCA-salt mice. The DOCA-salt mice received the agents via the CIV route for 10 days using an infusion minipump. DOCA-salt mice that received FGF23 showed a marked increase in the serum FGF23 level, and echocardiography in these mice revealed heart failure with a preserved ejection fraction. These mice also showed exacerbation of myocardial fibrosis, concomitant with an inverse and significant correlation with Cyp27b1 expression. Calcitriol treatment attenuated FGF23-induced cardiac fibrosis and improved diastolic function via inhibition of transforming growth factor-β signaling. This effect was independent of the systemic and local levels of FGF23. These results suggest that CIV FGF23 loading exacerbates cardiac fibrosis and that locally abnormal vitamin D metabolism is involved in this mechanism. Calcitriol attenuates this exacerbation by mediating transforming growth factor-β signaling independently of the FGF23 levels.
Topics: Animals; Male; Mice; Blood Pressure; Calcitriol; Desoxycorticosterone Acetate; Fibroblast Growth Factor-23; Fibrosis; Heart Failure; Hypertension; Renal Insufficiency, Chronic; Transforming Growth Factor beta; Transforming Growth Factors
PubMed: 36748187
DOI: 10.1016/j.labinv.2022.100003 -
Scientific Reports Jan 2020Circulating cells have a pathogenic role in the development of hypertensive nephropathy. However, how these cells infiltrate into the kidney are not fully elucidated. In...
Circulating cells have a pathogenic role in the development of hypertensive nephropathy. However, how these cells infiltrate into the kidney are not fully elucidated. In this study, we investigated the role of CXCR6 in deoxycorticosterone acetate (DOCA)/salt-induced inflammation and fibrosis of the kidney. Following uninephrectomy, wild-type and CXCR6 knockout mice were treated with DOCA/salt for 3 weeks. Blood pressure was similar between wild-type and CXCR6 knockout mice at baseline and after treatment with DOCA/salt. Wild-type mice develop significant kidney injury, proteinuria, and kidney fibrosis after three weeks of DOCA/salt treatment. CXCR6 deficiency ameliorated kidney injury, proteinuria, and kidney fibrosis following treatment with DOCA/salt. Moreover, CXCR6 deficiency inhibited accumulation of bone marrow-derived fibroblasts and myofibroblasts in the kidney following treatment with DOCA/salt. Furthermore, CXCR6 deficiency markedly reduced the number of macrophages and T cells in the kidney after DOCA/salt treatment. In summary, our results identify a critical role of CXCR6 in the development of inflammation and fibrosis of the kidney in salt-sensitive hypertension.
Topics: Animals; Blood Pressure; Desoxycorticosterone Acetate; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Gene Expression Regulation; Gene Knockout Techniques; Hypertension; Kidney; Macrophages; Mice; Receptors, CXCR6; Sodium Chloride, Dietary
PubMed: 31924817
DOI: 10.1038/s41598-019-56933-7 -
Journal of Hypertension May 2020Cannabidiol (CBD) has been suggested as a potential antihypertensive drug. The aim of our study was to investigate its vasodilatory effect in isolated human pulmonary...
OBJECTIVE
Cannabidiol (CBD) has been suggested as a potential antihypertensive drug. The aim of our study was to investigate its vasodilatory effect in isolated human pulmonary arteries (hPAs) and rat small mesenteric arteries (sMAs).
METHODS
Vascular effects of CBD were examined in hPAs obtained from patients during resection of lung carcinoma and sMAs isolated from spontaneously hypertensive (SHR); 11-deoxycorticosterone acetate (DOCA-salt) hypertensive rats or their appropriate normotensive controls using organ bath and wire myography, respectively.
RESULTS
CBD induced almost full concentration-dependent vasorelaxation in hPAs and rat sMAs. In hPAs, it was insensitive to antagonists of CB1 (AM251) and CB2 (AM630) receptors but it was reduced by endothelium denudation, cyclooxygenase inhibitors (indomethacin and nimesulide), antagonists of prostanoid EP4 (L161982), IP (Cay10441), vanilloid TRPV1 (capsazepine) receptors and was less potent under KCl-induced tone and calcium-activated potassium channel (KCa) inhibitors (iberiotoxin, UCL1684 and TRAM-34) and in hypertensive, overweight and hypercholesteremic patients. The time-dependent effect of CBD was sensitive to the PPARγ receptor antagonist GW9662. In rats, the CBD potency was enhanced in DOCA-salt and attenuated in SHR. The CBD-induced relaxation was inhibited in SHR and DOCA-salt by AM251 and only in DOCA-salt by AM630 and endothelium denudation.
CONCLUSION
The CBD-induced relaxation in hPAs that was reduced in hypertensive, obese and hypercholesteremic patients was endothelium-dependent and mediated via KCa and IP, EP4, TRPV1 receptors. The CBD effect in rats was CB1-sensitive and dependent on the hypertension model. Thus, modification of CBD-mediated responses in disease should be considered when CBD is used for therapeutic purposes.
Topics: Aged; Animals; Antihypertensive Agents; Blood Pressure; Cannabidiol; Desoxycorticosterone Acetate; Endothelium, Vascular; Female; Humans; Hypertension; Male; Mesenteric Arteries; Middle Aged; Pulmonary Artery; Rats; Rats, Inbred SHR; Vasodilation
PubMed: 31800399
DOI: 10.1097/HJH.0000000000002333 -
Journal of Veterinary Internal Medicine 2024An 18-month-old spayed female domestic short haired cat was presented for poor appetite, lethargy, exaggerated swallowing, and regurgitation 2 weeks after endoscopic...
CASE DESCRIPTION
An 18-month-old spayed female domestic short haired cat was presented for poor appetite, lethargy, exaggerated swallowing, and regurgitation 2 weeks after endoscopic retrieval of gastric foreign material.
CLINICAL FINDINGS
The cat was quiet with tacky mucous membranes on physical examination. Point-of-care blood testing identified mild azotemia, moderate hypercalcemia, and a sodium-to-potassium ratio of 26. An ultrasound examination the next day identified moderate to marked bilateral adrenomegaly. Cytology of a fine needle aspirate of the adrenal glands was consistent with necrosis and associated inflammation. Hypoadrenocorticism was diagnosed by a confirmatory adrenocorticotropic hormone stimulation test.
TREATMENT AND OUTCOME
The cat normalized both clinically and biochemically after treatment with prednisolone and desoxycorticosterone pivalate.
CLINICAL RELEVANCE
Acute adrenal necrosis has been well documented in human medicine after anesthetic events. To our knowledge, hypoadrenocorticism caused by cytologically confirmed acute adrenal necrosis has not been previously reported in dogs and cats.
Topics: Humans; Cats; Female; Animals; Dogs; Cat Diseases; Dog Diseases; Adrenal Insufficiency; Prednisolone; Hypercalcemia
PubMed: 37945312
DOI: 10.1111/jvim.16926 -
Genes Feb 2023In aquaculture, many stressors can negatively affect growth in teleosts. It is believed that cortisol performs glucocorticoid and mineralocorticoid functions because...
In aquaculture, many stressors can negatively affect growth in teleosts. It is believed that cortisol performs glucocorticoid and mineralocorticoid functions because teleosts do not synthesize aldosterone. However, recent data suggest that 11-deoxycorticosterone (DOC) released during stress events may be relevant to modulate the compensatory response. To understand how DOC modifies the skeletal muscle molecular response, we carried out a transcriptomic analysis. Rainbow trout () were intraperitoneally treated with physiological doses of DOC in individuals pretreated with mifepristone (glucocorticoid receptor antagonist) or eplerenone (mineralocorticoid receptor antagonist). RNA was extracted from the skeletal muscles, and cDNA libraries were constructed from vehicle, DOC, mifepristone, mifepristone plus DOC, eplerenone, and eplerenone plus DOC groups. The RNA-seq analysis revealed 131 differentially expressed transcripts (DETs) induced by DOC with respect to the vehicle group, mainly associated with muscle contraction, sarcomere organization, and cell adhesion. In addition, a DOC versus mifepristone plus DOC analysis revealed 122 DETs related to muscle contraction, sarcomere organization, and skeletal muscle cell differentiation. In a DOC versus eplerenone plus DOC analysis, 133 DETs were associated with autophagosome assembly, circadian regulation of gene expression, and regulation of transcription from RNA pol II promoter. These analyses indicate that DOC has a relevant function in the stress response of skeletal muscles, whose action is differentially modulated by GR and MR and is complementary to cortisol.
Topics: Animals; Oncorhynchus mykiss; Transcriptome; Desoxycorticosterone; Mifepristone; Eplerenone; Hydrocortisone; Muscle, Skeletal
PubMed: 36833439
DOI: 10.3390/genes14020512 -
Journal of Pediatric Endocrinology &... Aug 2022To explore the associations of environmental endocrine disruptors on precocious puberty in girls.
OBJECTIVES
To explore the associations of environmental endocrine disruptors on precocious puberty in girls.
METHODS
This was a case-control study in which 30 girls with precocious puberty and 46 age- and race-matched prepubertal females were enrolled. The concentrations of 10 environment endocrine disruptors (bisphenol A, bisphenol B, butylparaben, propylparaben, ethvlparaben, methylparaben, mono-butyl phthalate, mono-2-ethylhexyl phthalate, monoethyl phthalate, and monomethyl phthalate) in urine and 10 steroid hormones (dihydrotestosterone, corticosterone, hydrocortisone, 11-deoxycortisol, 17α-hydroxy progesterone, 4-androstene-3,17-dione, estrone, deoxycorticosterone, pregnenolone, and dehydroepiandrosterone) in serum were detected with the liquid chromatography-mass spectrometry (LC-MS).
RESULTS
According to the Mann-Whitney U test, urinary levels of bisphenol A, monobutyl phthalate, and monomethyl phthalate were significantly higher in the precocious group than in the prepubertal group, and blood levels of hydrocortisone, 11-deoxycortisol, corticosterone, deoxycorticosterone, and pregnenolone were significantly lower in the precocious group than in the prepubertal group (p<0.05, VIP>1).
CONCLUSIONS
Our findings confirm the association between phthalate exposure and the incidence of precocious puberty in girls. Control and reduction of children exposure to phthalate esters should be considered as a health priority.
Topics: Case-Control Studies; Child; Corticosterone; Cortodoxone; Desoxycorticosterone; Endocrine Disruptors; Environmental Exposure; Female; Humans; Hydrocortisone; Pregnenolone; Puberty, Precocious
PubMed: 35692072
DOI: 10.1515/jpem-2021-0691 -
American Journal of Physiology. Renal... Oct 2020Recently, we reported a mutation in γ-adducin (ADD3) was associated with an impaired myogenic response of the afferent arteriole and hypertension-induced chronic kidney...
Recently, we reported a mutation in γ-adducin (ADD3) was associated with an impaired myogenic response of the afferent arteriole and hypertension-induced chronic kidney disease (CKD) in fawn hooded hypertensive (FHH) rats. However, the mechanisms by which altered renal blood flow (RBF) autoregulation promotes hypertension-induced renal injury remain to be determined. The present study compared the time course of changes in renal hemodynamics and the progression of CKD during the development of DOCA-salt hypertension in FHH 1 congenic rats [wild-type (WT)] with an intact myogenic response versus FHH 1KO (KO) rats, which have impaired myogenic response. RBF was well autoregulated in WT rats but not in KO rats. Glomerular capillary pressure rose by 6 versus 14 mmHg in WT versus KO rats when blood pressure increased from 100 to 150 mmHg. After 1 wk of hypertension, glomerular filtration rate increased by 38% and glomerular nephrin expression decreased by 20% in KO rats. Neither were altered in WT rats. Proteinuria doubled in WT rats versus a sixfold increase in KO rats. The degree of renal injury was greater in KO than WT rats after 3 wk of hypertension. RBF, glomerular filtration rate, and glomerular capillary pressure were lower by 20%, 28%, and 19% in KO rats than in WT rats, which was associated with glomerular matrix expansion and loss of capillary filtration area. The results indicated that impaired RBF autoregulation and eutrophic remodeling of preglomerular arterioles increase the transmission of pressure to glomeruli, which induces podocyte loss and accelerates the progression of CKD in hypertensive KO rats.
Topics: Animals; Arterioles; Blood Pressure; Calmodulin-Binding Proteins; Desoxycorticosterone Acetate; Disease Models, Animal; Disease Progression; Glomerular Filtration Rate; Homeostasis; Hypertension; Kidney Glomerulus; Male; Muscle Development; Muscle, Smooth, Vascular; Proteinuria; Rats, Transgenic; Renal Circulation; Renal Insufficiency, Chronic; Sodium Chloride, Dietary; Vascular Remodeling
PubMed: 32830539
DOI: 10.1152/ajprenal.00239.2020 -
Hypertension (Dallas, Tex. : 1979) Nov 2021IL-18 (interleukin-18) is elevated in hypertensive patients, but its contribution to high blood pressure and end-organ damage is unknown. We examined the role of IL-18...
IL-18 (interleukin-18) is elevated in hypertensive patients, but its contribution to high blood pressure and end-organ damage is unknown. We examined the role of IL-18 in the development of renal inflammation and injury in a mouse model of low-renin hypertension. Hypertension was induced in male C57BL6/J (WT) and IL-18−/− mice by uninephrectomy, deoxycorticosterone acetate (2.4 mg/d, s.c.) and 0.9% drinking saline (1K/DOCA/salt). Normotensive controls received uninephrectomy and placebo (1K/placebo). Blood pressure was measured via tail cuff or radiotelemetry. After 21 days, kidneys were harvested for (immuno)histochemical, quantitative-PCR and flow cytometric analyses of fibrosis, inflammation, and immune cell infiltration. 1K/DOCA/salt-treated WT mice developed hypertension, renal fibrosis, upregulation of proinflammatory genes, and accumulation of CD3+ T cells in the kidneys. They also displayed increased expression of IL-18 on tubular epithelial cells. IL-18−/− mice were profoundly protected from hypertension, renal fibrosis, and inflammation. Bone marrow transplantation between WT and IL-18−/− mice revealed that IL-18-deficiency in non-bone marrow-derived cells alone afforded equivalent protection against hypertension and renal injury as global IL-18 deficiency. IL-18 receptor subunits—interleukin-18 receptor 1 and IL-18R accessory protein—were upregulated in kidneys of 1K/DOCA/salt-treated WT mice and localized to T cells and tubular epithelial cells. T cells from kidneys of 1K/DOCA/salt-treated mice produced interferon-γ upon ex vivo stimulation with IL-18, whereas those from 1K/placebo mice did not. In conclusion, IL-18 production by tubular epithelial cells contributes to elevated blood pressure, renal inflammation, and fibrosis in 1K/DOCA/salt-treated mice, highlighting it as a promising therapeutic target for hypertension and kidney disease.
Topics: Albuminuria; Animals; Blood Pressure; Desoxycorticosterone Acetate; Epithelial Cells; Hypertension; Inflammation; Interleukin-18; Kidney; Kidney Diseases; Kidney Tubules; Male; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes; Mice
PubMed: 34488433
DOI: 10.1161/HYPERTENSIONAHA.120.16437