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British Journal of Pharmacology Mar 2021Fibrosis is a hallmark of chronic kidney disease (CKD) that significantly contributes to renal dysfunction, and impairs the efficacy of stem cell-based therapies. This...
BACKGROUND AND PURPOSE
Fibrosis is a hallmark of chronic kidney disease (CKD) that significantly contributes to renal dysfunction, and impairs the efficacy of stem cell-based therapies. This study determined whether combining bone marrow-derived mesenchymal stem cells (BM-MSCs) with the renoprotective effects of recombinant human relaxin (serelaxin) could therapeutically reduce renal fibrosis in mice with one kidney/deoxycorticosterone acetate/salt (1K/DOCA/salt)-induced hypertension, compared with the effects of the ACE inhibitor, perindopril.
EXPERIMENTAL APPROACH
Adult male C57BL/6 mice were uni-nephrectomised and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt) for 21 days. Control mice were uni-nephrectomised but received water over the same time period. Sub-groups of 1K/DOCA/salt-injured mice (n = 5-8 per group) were treated with either serelaxin (0.5 mg·kg ·day ) or BM-MSCs (1 × 10 per mouse) alone; both treatments combined (with 0.5 × 10 or 1 × 10 BM-MSCs per mouse); or perindopril (2 mg·kg ·day ) from days 14-21.
KEY RESULTS
1K/DOCA/salt-injured mice developed elevated BP and hypertension-induced renal damage, inflammation and fibrosis. BM-MSCs alone reduced the injury-induced fibrosis and attenuated BP to a similar extent as perindopril. Serelaxin alone modestly reduced renal fibrosis and effectively reduced tubular injury. Strikingly, the combined effects of BM-MSCs (at both doses) with serelaxin significantly inhibited renal fibrosis and proximal tubular epithelial injury while restoring renal architecture, to a greater extent than either therapy alone, and over the effects of perindopril.
CONCLUSION AND IMPLICATIONS
Combining BM-MSCs and serelaxin provided broader renoprotection over either therapy alone or perindopril and might represent a novel treatment for hypertensive CKD.
Topics: Animals; Blood Pressure; Desoxycorticosterone; Desoxycorticosterone Acetate; Hypertension; Hypertension, Renal; Kidney; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL
PubMed: 33450051
DOI: 10.1111/bph.15361 -
Clinical and Experimental Pharmacology... Apr 2021Hypertension is a multifaceted condition influenced by genetic and environmental factors and estimated to cause 9.4 million deaths globally every year. Recently, there...
Hypertension is a multifaceted condition influenced by genetic and environmental factors and estimated to cause 9.4 million deaths globally every year. Recently, there has been growing interest in understanding the gut microbe-host interaction in the maintenance of health or disease states, but relatively few studies have shown an association between the gut microbiome and specific types of hypertension. The deoxycorticosterone acetate (DOCA)-salt model of hypertension in rats is known to have a neurogenic component linked to increased sympathetic nervous system activity. As such, our lab has recently shown the hypertensive response in DOCA treated rats requires an intact organum vasculosum of the lamina terminalis (OVLT), a central hypothalamic circumventricular organ. Currently, we hypothesize the OVLT mediates changes in the gut microbiome associated with concomitant hypertension. Herein, we report that the hypertensive effects of DOCA-salt treatment were significantly attenuated throughout the 24-hour day/night cycle in OLVT lesioned rats on days 1, 3, and 9-21 of DOCA treatment compared with sham rats. Increased blood pressure (BP) in DOCA-salt treated rats was accompanied by specific changes in regional gut microbial populations yet was mitigated and offset by lesion of the OVLT. Furthermore, bacterial populations in OVLT-lesioned rats with attenuated hypertension more closely resembled those in normal control rats. We conclude that DOCA-salt hypertension is associated with specific microbiome changes in the gut, and the attenuated hypertensive effects of DOCA-salt in OVLT-lesioned rats is mediated in part through counteracting changes in these bacterial populations.
Topics: Animals; Blood Pressure; Desoxycorticosterone Acetate; Gastrointestinal Microbiome; Hypertension; Organum Vasculosum; Rats
PubMed: 33462863
DOI: 10.1111/1440-1681.13457 -
Scientific Reports May 2023Stress increases plasma concentrations of corticosteroids, however, their tissue levels are unclear. Using a repeated social defeat paradigm, we examined the impact of...
Stress increases plasma concentrations of corticosteroids, however, their tissue levels are unclear. Using a repeated social defeat paradigm, we examined the impact of chronic stress on tissue levels of corticosterone (CORT), progesterone (PROG), 11-deoxycorticosterone (11DOC) and 11-dehydrocorticosterone (11DHC) and on gut microbiota, which may reshape the stress response. Male BALB/c mice, liquid chromatography-tandem mass spectrometry and 16S RNA gene sequencing were used to screen steroid levels and fecal microbiome, respectively. Stress induced greater increase of CORT in the brain, liver, and kidney than in the colon and lymphoid organs, whereas 11DHC was the highest in the colon, liver and kidney and much lower in the brain and lymphoid organs. The CORT/11DHC ratio in plasma was similar to the brain but much lower in other organs. Stress also altered tissue levels of PROG and 11DOC and the PROG/11DOC ratio was much higher in lymphoid organs that in plasma and other organs. Stress impacted the β- but not the α-diversity of the gut microbiota and LEfSe analysis revealed several biomarkers associated with stress treatment. Our data indicate that social defeat stress modulates gut microbiota diversity and induces tissue-dependent changes in local levels of corticosteroids, which often do not reflect their systemic levels.
Topics: Mice; Animals; Male; Corticosterone; Progesterone; Desoxycorticosterone; Steroids; Brain; Chromatography, Liquid
PubMed: 37142643
DOI: 10.1038/s41598-023-34395-2 -
International Journal of Molecular... Dec 2023Hypertension is a global civilization disease and one of the most common causes of death in the world. Organ dysfunction is a serious health consequence of hypertension,...
Evaluation of the Expression and Localization of the Multifunctional Protein CacyBP/SIP and Elements of the MAPK Signaling Pathway in the Adrenal Glands of Rats with Primary and Secondary Hypertension.
Hypertension is a global civilization disease and one of the most common causes of death in the world. Organ dysfunction is a serious health consequence of hypertension, which involves damage to the heart, kidneys and adrenals. The interaction of recently discovered multifunctional protein-CacyBP/SIP with ERK1/2 and p38 kinases by regulating the activity and intracellular localization of these kinases may play an important role in the signaling pathways involved in the pathogenesis of hypertension. Due to the lack of data on this subject, we decided to investigate the localization, expression and possible relationship between the studied parameters in the adrenals under arterial hypertension. The study was conducted on the adrenals of rats with spontaneous and DOCA-salt hypertension. The expression of CacyBP/SIP, p-ERK1/2 and p-p38 was detected by immunohistochemistry and qRT-PCR. The results show a statistically significant decrease in CacyBP/SIP expression in the adrenal glands of hypertensive rats. With ERK1/2, there was a decrease in cortical immunoreactivity and an increase in the adrenal medulla of primary hypertensive rats. In contrast, in the adrenals of DOCA-salt rats, ERK1/2 immunoreactivity increased in the cortex and decreased in the medulla. In turn, p38 expression was higher in the adrenal glands of rats with primary and secondary hypertension. The obtained results may suggest the involvement of CacyBP/SIP in the regulation of signaling pathways in which MAP kinases play an important role and provide new insight into molecular events in hypertension. Moreover, they show the participation of CacyBP/SIP in response to oxidative stress.
Topics: Animals; Rats; MAP Kinase Signaling System; Desoxycorticosterone Acetate; Signal Transduction; Adrenal Glands; Hypertension; Sodium Chloride; Sodium Chloride, Dietary; Intracellular Signaling Peptides and Proteins
PubMed: 38203261
DOI: 10.3390/ijms25010084 -
Experimental Physiology Feb 2023What is the central question of this study? Are renal functional responses to intrarenal angiotensin 1-7 (Ang (1-7)) infusion dependent on the level of the endogenous...
Effects of intrarenal angiotensin 1-7 infusion on renal haemodynamic and excretory function in anaesthetised two-kidney one-clip and deoxycorticosterone acetate-salt hypertensive rats.
NEW FINDINGS
What is the central question of this study? Are renal functional responses to intrarenal angiotensin 1-7 (Ang (1-7)) infusion dependent on the level of the endogenous renin-angiotensin system (RAS) in the two-kidney one-clip (2K1C) and deoxycorticosterone acetate (DOCA)-salt animal models of hypertension? What is the main finding and its importance? The renal actions of Ang (1-7) are dependent on the relative endogenous levels of each arm of the classical angiotensin II-angiotensin II type 1 receptor (AT R) axis and those of the Ang (1-7)-Mas receptor axis. These findings support the hypothesis that a balance exists between the intrarenal classical and novel arms of the RAS, and in particular the relative abundance of AT R to Mas receptor, which may to a large extent determine the renal excretory response to Ang (1-7) infusion.
ABSTRACT
This study investigated the action of angiotensin 1-7 (Ang (1-7)) on renal haemodynamic and excretory function in the two-kidney one-clip (2K1C) and deoxycorticosterone acetate (DOCA)-salt rat models of hypertension, in which the endogenous renin-angiotensin system (RAS) activity was likely to be raised or lowered, respectively. Rats were anaesthetised and prepared for the measurement of mean arterial pressure and kidney function during renal interstitial infusion of Ang (1-7) or saline. Kidney tissue concentrations of angiotensin II (Ang II) and Ang (1-7) were determined. Intrarenal infusion of Ang (1-7) into the clipped kidney of 2K1C rats increased urine flow (UV), absolute (U V) and fractional sodium (FE ) excretions by 110%, 214% and 147%, respectively. Renal Ang II concentrations of the clipped kidney were increased with no major changes in Ang (1-7) concentration. By contrast, Ang (1-7) infusion decreased UV, U V, and FE by 27%, 24% and 21%, respectively in the non-clipped kidney in which tissue Ang (1-7) concentrations were increased, but renal Ang II concentrations were unchanged compared to sham animals. Ang (1-7) infusion in DOCA-salt rats had minimal effects on glomerular filtration rate but significantly decreased UV, U V and FE by ∼30%. Renal Ang (1-7) concentrations were higher and Ang II concentrations were lower in DOCA-salt rats compared to sham rats. These findings demonstrate that the intrarenal infusion of exogenous Ang (1-7) elicits different renal excretory responses the magnitude of which is dependent on the balance between the endogenous renal Ang II-AT receptor axis and Ang (1-7)-Mas receptor axis.
Topics: Rats; Animals; Angiotensin II; Desoxycorticosterone Acetate; Kidney; Hypertension; Hemodynamics; Acetates
PubMed: 36454195
DOI: 10.1113/EP090791 -
Translational Psychiatry Jun 2022There is preliminary evidence that adrenal steroids other than cortisol may be valuable biomarkers for major depressive disorder (MDD). So far, studies have been...
There is preliminary evidence that adrenal steroids other than cortisol may be valuable biomarkers for major depressive disorder (MDD). So far, studies have been conducted in adults only, and conclusions are limited, mainly due to small sample sizes. Therefore, the present study assessed whether adrenal steroids serve as biomarkers for adolescent MDD. In 261 depressed adolescents (170 females) treated at a single psychiatric hospital, serum adrenal steroids (progesterone, 17-hydroxyprogesterone, 21-deoxycortisol, 11-deoxycortisol, cortisol, cortisone, deoxycorticosterone, corticosterone) were determined by liquid chromatography-tandem mass spectrometry. Findings were compared to that of an age- and sex-matched reference cohort (N = 255) by nonparametric analysis of variance. Nonparametric receiver operating characteristics (ROC) analyses were conducted to evaluate the diagnostic performance of single steroids and steroid ratios to classify depression status. Sensitivity analyses considered important confounders of adrenal functioning, and ROC results were verified by cross-validation. Compared to the reference cohort, levels of deoxycorticosterone and 21-deoxycortisol were decreased (P < 0.001). All other glucocorticoid- and mineralocorticoid-related steroids were increased (P < 0.001). The corticosterone to deoxycorticosterone ratio evidenced excellent classification characteristics, especially in females (AUC: 0.957; sensitivity: 0.902; specificity: 0.891). The adrenal steroid metabolome qualifies as a bio-readout reflecting adolescent MDD by a distinct steroid pattern that indicates dysfunction of the hypothalamus-pituitary-adrenal axis. Moreover, the corticosterone to deoxycorticosterone ratio may prospectively qualify to contribute to precision medicine in psychiatry by identifying those patients who might benefit from antiglucocorticoid treatment or those at risk for recurrence when adrenal dysfunction has not resolved.
Topics: Adolescent; Adult; Corticosterone; Depression; Depressive Disorder, Major; Desoxycorticosterone; Female; Humans; Hydrocortisone; Steroids
PubMed: 35717450
DOI: 10.1038/s41398-022-01966-2 -
American Journal of Hypertension Aug 2023Our previous studies showed that renal medullary sphingosine-1-phosphate receptor 1 (S1PR1) mediated sodium excretion, high salt intake increased S1PR1 level,...
BACKGROUND
Our previous studies showed that renal medullary sphingosine-1-phosphate receptor 1 (S1PR1) mediated sodium excretion, high salt intake increased S1PR1 level, deoxycorticosterone acetate (DOCA) blocked high salt-induced S1PR1 in the renal medulla, and that conditional knockout of S1PR1 in the collecting duct aggravated DOCA-salt hypertension. The present study tested the hypothesis that overexpression of S1PR1 transgene in the renal medulla attenuates the sodium retention and hypertension in DOCA-salt mouse model.
METHODS
Male C57BL/6J mice received renal medullary transfection of control or S1PR1-expressing plasmids and then DOCA-salt treatment. Renal sodium excretion and arterial pressure were compared between control and S1PR1-overexpressed mice in response to high salt loading or pressure natriuresis.
RESULTS
S1PR1-transfected mice showed significantly enhanced urinary sodium excretion in response to acute sodium loading (0.93 ± 0.27 in control vs. 4.72 ± 1.12 µmol/min/gKW in S1PR1-overexpressed mice, P < 0.05) and the pressure natriuresis (3.58 ± 1.77 vs. 9.52 ± 1.38, P < 0.05), less positive sodium balance in response to chronic high-salt intake (3.05 ± 0.39 vs. 1.65 ± 0.39 mmol/72 hr, P < 0.05), and consequently, the attenuation of DOCA-salt hypertension (134.2 ± 6.79 vs. 109.8 ± 3.54 mm Hg, P < 0.05). The αENaC protein amount in the renal medulla was not changed, however, the βENaC was significantly decreased and the γENaC was significantly increased in S1PR1-overexpressed mice. The immunostaining showed apical membrane translocation of γENaC, while no change of αENaC and βENaC in control mice, and that the apical membrane translocation of γENaC was blocked in S1PR1-treasffected mice.
CONCLUSIONS
These results suggested that activation of S1PR1 in the renal medulla attenuates DOCA-induced sodium retention and salt-sensitive hypertension associated with inhibition of ENaC.
Topics: Male; Mice; Animals; Desoxycorticosterone Acetate; Sodium Chloride, Dietary; Sphingosine-1-Phosphate Receptors; Mice, Inbred C57BL; Hypertension; Blood Pressure; Sodium; Sodium Chloride; Transgenes; Acetates; Kidney
PubMed: 37171128
DOI: 10.1093/ajh/hpad046 -
Metabolism: Clinical and Experimental May 2022High salt intake and aldosterone are both associated with vascular stiffening in humans. However, our preliminary work showed that high dietary salt alone did not...
INTRODUCTION
High salt intake and aldosterone are both associated with vascular stiffening in humans. However, our preliminary work showed that high dietary salt alone did not increase endothelial cell (EC) or vascular stiffness or endothelial sodium channel (EnNaC) activation in mice, presumably because aldosterone production was significantly suppressed as a result of the high salt diet. We thus hypothesized that high salt consumption along with an exogenous mineralocorticoid would substantially increase EC and vascular stiffness via activation of the EnNaC.
METHODS AND RESULTS
Mice were implanted with slow-release DOCA pellets and given salt in their drinking water for 21 days. Mice with either specific deletion of the alpha subunit of EnNaC or treated with a pharmacological inhibitor of mTOR, a downstream signaling molecule involved in mineralocorticoid receptor activation of EnNaC, were studied. DOCA-salt treated control mice had increased blood pressure, EC Na transport activity, EC and arterial stiffness, which were attenuated in both the αEnNaC and mTOR inhibitor treated groups. Further, depletion of αEnNaC prevented DOCA-salt-induced impairment in EC-dependent vascular relaxation.
CONCLUSION
While high salt consumption alone does not cause EC or vascular stiffening, the combination of EC MR activation and high salt causes activation of EnNaC which increases EC and arterial stiffness and impairs vascular relaxation. Underlying mechanisms appear to include mTOR signaling.
Topics: Animals; Blood Pressure; Desoxycorticosterone Acetate; Endothelial Cells; Epithelial Sodium Channels; Hypertension; Mice; Sodium; Vascular Stiffness
PubMed: 35183546
DOI: 10.1016/j.metabol.2022.155165 -
Biomolecules Aug 2022The brain renin-angiotensin system plays important roles in blood pressure and cardiovascular regulation. There are two isoforms of prorenin in the brain: the classic...
The brain renin-angiotensin system plays important roles in blood pressure and cardiovascular regulation. There are two isoforms of prorenin in the brain: the classic secreted form (prorenin/sREN) encoded by renin-a, and an intracellular form (icREN) encoded by renin-b. Emerging evidence indicates the importance of renin-b in cardiovascular and metabolic regulation. However, the role of endogenous brain prorenin in the development of salt-sensitive hypertension remains undefined. In this study, we test the hypothesis that renin-a produced locally in the brain contributes to the pathogenesis of hypertension. Using RNAscope, we report for the first time that renin mRNA is expressed in several regions of the brain, including the subfornical organ (SFO), the paraventricular nucleus of the hypothalamus (PVN), and the brainstem, where it is found in glutamatergic, GABAergic, cholinergic, and tyrosine hydroxylase-positive neurons. Notably, we found that renin mRNA was significantly elevated in the SFO and PVN in a mouse model of DOCA-salt-induced hypertension. To examine the functional importance of renin-a in the SFO, we selectively ablated renin-a in the SFO in renin-a-floxed mice using a Cre-lox strategy. Importantly, renin-a ablation in the SFO attenuated the maintenance of DOCA-salt-induced hypertension and improved autonomic function without affecting fluid or sodium intake. Molecularly, ablation of renin-a prevented the DOCA-salt-induced elevation in NADPH oxidase 2 (NOX2) in the SFO without affecting NOX4 or angiotensin II type 1 and 2 receptors. Collectively, our findings demonstrate that endogenous renin-a within the SFO is important for the pathogenesis of salt-sensitive hypertension.
Topics: Angiotensin II; Animals; Cholinergic Agents; Desoxycorticosterone Acetate; Hypertension; Mice; NADPH Oxidase 2; RNA, Messenger; Renin; Sodium Chloride; Sodium, Dietary; Subfornical Organ; Tyrosine 3-Monooxygenase
PubMed: 36139008
DOI: 10.3390/biom12091169 -
Biomedicine & Pharmacotherapy =... Jan 2024Heart failure (HF) preserved ejection fraction (HFpEF) accounts for almost 50% of HF, and hypertension is one of the pathogenies. The MAPK signaling pathway is closely...
Heart failure (HF) preserved ejection fraction (HFpEF) accounts for almost 50% of HF, and hypertension is one of the pathogenies. The MAPK signaling pathway is closely linked to heart failure and hypertension; however, its function in HEpEF resulting from salt-sensitive hypertension is not well understood. In this work, a salt-sensitive hypertension-induced HEpEF model was established based on deoxycorticosterone acetate-salt (DOCA-salt) hypertension mice. The impact of the MAPK inhibitor (Doramapimod) on HEpEF induced by salt-sensitive hypertension was assessed through various measures, such as blood pressure, transthoracic echocardiography, running distance, and histological analysis, to determine its therapeutic effectiveness on cardiac function. In addition, the effects of high salt on myogenic cells were also evaluated in vitro using qRTPCR. The LV ejection fractions (LVEF) in DOCA-salt hypertension mice were over 50%, indicating that the salt-sensitive hypertension-induced HFpEF model was successful. RNA-seq revealed that the MAPK signaling pathway was upregulated in the HFpEF model compared with the normal mice, accompanied by hypertension, impaired running distance, restricted cardiac function, increased cross-sectional and fibrosis area, and upregulation of heart failure biomarkers, including GAL-3, LDHA and BNP. The application of Doramapimod could improve blood pressure, cardiomyocyte hypertrophy, and myocardial fibrosis, as well as decrease the aforementioned heart failure biomarkers. The qRTPCR results showed similar findings to these observations. Our findings suggest that the use of a MAPK inhibitor (Doramapimod) could be a potential treatment for salt-sensitive hypertension-induced HFpEF.
Topics: Mice; Animals; Heart Failure; Stroke Volume; Desoxycorticosterone Acetate; Cross-Sectional Studies; Hypertension; Sodium Chloride, Dietary; Fibrosis; Biomarkers
PubMed: 38056241
DOI: 10.1016/j.biopha.2023.115987