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Journal of Advanced Research Jan 2024Leukocyte infiltration is an early event during cardiac remodeling frequently leading to heart failure (HF). Integrins mediate leukocyte infiltration during...
INTRODUCTION
Leukocyte infiltration is an early event during cardiac remodeling frequently leading to heart failure (HF). Integrins mediate leukocyte infiltration during inflammation. However, the importance of specific integrins in hypertensive cardiac remodeling is still unclear.
OBJECTIVES
To elucidate the significance of CD11b in hypertensive cardiac remodeling.
METHODS
Angiotensin (Ang II) or deoxycorticosterone acetate (DOCA)-salt was used to induce cardiac remodeling in mice of gene knockout (KO), bone marrow (BM) chimera, and the CD11b neutralizing antibody or agonist leukadherin-1 (LA1) treatment.
RESULTS
Our microarray data showed that integrin subunits Itgam (CD11b) and Itgb2 (CD18) were the most highly upregulated in Ang II-infused hearts. CD11b expression and CD11b/CD18 myelomonocytes were also time-dependently increased. KO or pharmacological blockade of CD11b greatly attenuated cardiac remodeling and macrophage infiltration and M1 polarization induced by Ang II or DOCA-salt. This protection was verified in wild-type mice transplanted with CD11b-deficient BM cells. Conversely, administration of CD11b agonist LA1 showed the opposite effects. Further, CD11b KO reduced Ang II-induced macrophage adhesion and M1 polarization, leading to reduction of cardiomyocyte enlargement and fibroblast differentiation in vitro. The numbers of CD14CD11bCD18 monocytes and CD15CD11bCD18 granulocytes were obviously higher in HF patients than in normal controls.
CONCLUSION
Our data demonstrate an important role of CD11b myeloid cells in hypertensive cardiac remodeling, and suggest that HF may benefit from targeting CD11b.
Topics: Humans; Animals; Mice; Ventricular Remodeling; Desoxycorticosterone Acetate; Macrophages; Hypertension; Heart Failure; Integrins
PubMed: 36822392
DOI: 10.1016/j.jare.2023.02.010 -
Circulation Research May 2022Renal T cells contribute importantly to hypertension, but the underlying mechanism is incompletely understood. We reported that CD8Ts directly stimulate distal...
BACKGROUND
Renal T cells contribute importantly to hypertension, but the underlying mechanism is incompletely understood. We reported that CD8Ts directly stimulate distal convoluted tubule cells (DCTs) to increase NCC (sodium chloride co-transporter) expression and salt reabsorption. However, the mechanistic basis of this pathogenic pathway that promotes hypertension remains to be elucidated.
METHODS
We used mouse models of DOCA+salt (DOCA) treatment and adoptive transfer of CD8 T cells (CD8T) from hypertensive animals to normotensive animals in in vivo studies. Co-culture of mouse DCTs and CD8Ts was used as in vitro model to test the effect of CD8T activation in promoting NCC-mediated sodium retention and to identify critical molecular players contributing to the CD8T-DCT interaction. Interferon (IFNγ)-KO mice and mice receiving renal tubule-specific knockdown of PDL1 were used to verify in vitro findings. Blood pressure was continuously monitored via radio-biotelemetry, and kidney samples were saved at experimental end points for analysis.
RESULTS
We identified critical molecular players and demonstrated their roles in augmenting the CD8T-DCT interaction leading to salt-sensitive hypertension. We found that activated CD8Ts exhibit enhanced interaction with DCTs via IFN-γ-induced upregulation of MHC-I and PDL1 in DCTs, thereby stimulating higher expression of NCC in DCTs to cause excessive salt retention and progressive elevation of blood pressure. Eliminating IFN-γ or renal tubule-specific knockdown of PDL1 prevented T cell homing into the kidney, thereby attenuating hypertension in 2 different mouse models.
CONCLUSIONS
Our results identified the role of activated CD8Ts in contributing to increased sodium retention in DCTS through the IFNγ-PDL1 pathway. These findings provide a new mechanism for T cell involvement in the pathogenesis of hypertension and reveal novel therapeutic targets.
Topics: Animals; CD8-Positive T-Lymphocytes; Desoxycorticosterone Acetate; Disease Models, Animal; Hypertension; Kidney Tubules, Distal; Mice; Sodium; Sodium Chloride Symporters; Sodium Chloride, Dietary
PubMed: 35430873
DOI: 10.1161/CIRCRESAHA.121.320373 -
American Journal of Physiology. Renal... Apr 2024Patients with hypertension or obesity can develop glomerular dysfunction characterized by injury and depletion of podocytes. To better understand the molecular processes...
Patients with hypertension or obesity can develop glomerular dysfunction characterized by injury and depletion of podocytes. To better understand the molecular processes involved, young mice were treated with either deoxycorticosterone acetate (DOCA) or fed a high-fat diet (HFD) to induce hypertension or obesity, respectively. The transcriptional changes associated with these phenotypes were measured by unbiased bulk mRNA sequencing of isolated podocytes from experimental models and their respective controls. Key findings were validated by immunostaining. In addition to a decrease in canonical proteins and reduced podocyte number, podocytes from both hypertensive and obese mice exhibited a sterile inflammatory phenotype characterized by increases in NLR family pyrin domain containing 3 (NLRP3) inflammasome, protein cell death-1, and Toll-like receptor pathways. Finally, although the mice were young, podocytes in both models exhibited increased expression of senescence and aging genes, including genes consistent with a senescence-associated secretory phenotype. However, there were differences between the hypertension- and obesity-associated senescence phenotypes. Both show stress-induced podocyte senescence characterized by increased and . Moreover, in hypertensive mice, this is superimposed upon age-associated podocyte senescence characterized by increased and . These results suggest that senescence, aging, and inflammation are critical aspects of the podocyte phenotype in experimental hypertension and obesity in mice. Hypertension and obesity can lead to glomerular dysfunction in patients, causing podocyte injury and depletion. Here, young mice given deoxycorticosterone acetate or a high-fat diet to induce hypertension or obesity, respectively. mRNA sequencing of isolated podocytes showed transcriptional changes consistent with senescence, a senescent-associated secretory phenotype, and aging, which was confirmed by immunostaining. Ongoing studies are determining the mechanistic roles of the accelerated aging podocyte phenotype in experimental hypertension and obesity.
Topics: Humans; Mice; Animals; Aged; Podocytes; Mice, Obese; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; Phenotype; Kidney Diseases; Obesity; Hypertension; Desoxycorticosterone; Acetates; RNA, Messenger
PubMed: 38420674
DOI: 10.1152/ajprenal.00417.2023 -
Hypertension (Dallas, Tex. : 1979) Nov 2022GPCRs (G protein-coupled receptors) are implicated in blood pressure (BP) and fluid intake regulation. There is a developing concept that these effects are mediated by...
BACKGROUND
GPCRs (G protein-coupled receptors) are implicated in blood pressure (BP) and fluid intake regulation. There is a developing concept that these effects are mediated by both canonical G protein signaling and noncanonical β-arrestin mediated signaling, but the contributions of each remain largely unexplored. Here, we hypothesized that β-arrestin contributes to fluid homeostasis and blood pressure (BP) regulation in deoxycorticosterone acetate (DOCA) salt hypertension, a prototypical model of salt-sensitive hypertension.
METHODS
Global β-arrestin1 () and β-arrestin2 () knockout mice were employed to evaluate drinking behavior, and BP was evaluated in -knockout mice. Age- and sex-matched C57BL/6 mice served as controls. We measured intake of water and different sodium chloride solutions and BP employing a 2-bottle choice paradigm with and without DOCA.
RESULTS
Without DOCA (baseline), -knockout mice exhibited a significant elevation in saline intake with no change in water intake. With DOCA treatment, -knockout mice exhibited a significant increase in both saline and water intake. Although -knockout mice exhibited hypernatremia at baseline conditions, we did not find significant changes in total body sodium stores or sodium palatability. In a separate cohort, BP was measured via telemetry in -knockout and C57BL/6 mice with and without DOCA. -knockout did not exhibit significant differences in BP before DOCA treatment when provided water alone, or when provided a choice of water and saline. However, -knockout exhibited an increased pressor response to DOCA-salt.
CONCLUSIONS
These findings suggest that in salt-sensitive hypertension, ARRB2, but not ARRB1 (β-arrestin 1), might counterbalance the canonical signaling of GPCRs.
Topics: Animals; Mice; Blood Pressure; Desoxycorticosterone Acetate; beta-Arrestin 2; Mice, Inbred C57BL; Hypertension; Sodium Chloride, Dietary; Sodium Chloride; Sodium; beta-Arrestins; Mice, Knockout; Homeostasis; Water; Desoxycorticosterone
PubMed: 36215165
DOI: 10.1161/HYPERTENSIONAHA.122.19863 -
American Journal of Veterinary Research Aug 2023To determine if urine electrolyte assessments can be used to monitor the adequacy of mineralocorticoid therapy in dogs with hypoadrenocorticism (HA).
OBJECTIVE
To determine if urine electrolyte assessments can be used to monitor the adequacy of mineralocorticoid therapy in dogs with hypoadrenocorticism (HA).
ANIMALS
29 dogs with naturally occurring glucocorticoid- and mineralocorticoid-deficient HA.
PROCEDURES
Urine sodium and potassium concentrations, sodium-to-potassium ratios, sodium-to-creatinine ratios, and potassium-to-creatinine (K:Cr) ratios were evaluated in dogs with newly diagnosed HA that were treated with desoxycorticosterone pivalate (DOCP). Dogs underwent measurements of urine and serum sodium, potassium, and creatinine concentrations and plasma renin activities twice monthly for up to 3 months. Regression analyses and calculation of coefficients of determination (R2) were performed to investigate potential associations between urine and serum variables. Urine variables also were compared between dogs considered to be undertreated or overtreated based on plasma renin activities.
RESULTS
Urine K:Cr ratios were significantly associated with serum potassium concentrations 10 to 14 days (P = .002) and 30 days (P = .027) after the initial DOCP injection, but R2 values were only 0.35 and 0.17, respectively. Urine K:Cr ratios (median [IQR]) also were higher in dogs that were overtreated with DOCP (1.3 [0.7 to 2.3]) as compared to those dogs that were undertreated with DOCP (0.8 [0.5 to 0.9]) at 10 to 14 days after the initial DOCP injection (P = .039) but not at 30 days after the initial injection. Other urine variables were not significantly different between undertreated and overtreated dogs.
CLINICAL RELEVANCE
Measures of urine electrolytes were not useful for assessing the adequacy of mineralocorticoid therapy in HA dogs that were treated with DOCP.
Topics: Dogs; Animals; Mineralocorticoids; Creatinine; Renin; Dog Diseases; Adrenal Insufficiency; Potassium; Electrolytes; Sodium
PubMed: 37279885
DOI: 10.2460/ajvr.23.02.0042 -
The Journal of Physiology May 2022Recently, studies have emerged suggesting that the skin plays a role as major Na reservoir via regulation of the content of glycosaminoglycans and osmotic gradients. We...
Recently, studies have emerged suggesting that the skin plays a role as major Na reservoir via regulation of the content of glycosaminoglycans and osmotic gradients. We investigated whether there were electrolyte gradients in skin and where Na could be stored to be inactivated from a fluid balance viewpoint. Na accumulation was induced in rats by a high salt diet (HSD) (8% NaCl and 1% saline to drink) or by implantation of a deoxycorticosterone acetate (DOCA) tablet (1% saline to drink) using rats on a low salt diet (LSD) (0.1% NaCl) on tap water as control. Na and K were assessed by ion chromatography in tissue eluates, and the extracellular volume by equilibration of Cr-EDTA. By tangential sectioning of the skin, we found a low Na content and extracellular volume in epidermis, both parameters rising by ∼30% and 100%, respectively, in LSD and even more in HSD and DOCA when entering dermis. We found evidence for an extracellular Na gradient from epidermis to dermis shown by an estimated concentration in epidermis ∼2 and 4-5 times that of dermis in HSD and DOCA-salt. There was intracellular storage of Na in skin, muscle, and myocardium without a concomitant increase in hydration. Our data suggest that there is a hydration-dependent high interstitial fluid Na concentration that will contribute to the skin barrier and thus be a mechanism for limiting water loss. Salt stress results in intracellular storage of Na in exchange with K in skeletal muscle and myocardium that may have electromechanical consequences. KEY POINTS: Studies have suggested that Na can be retained or removed without commensurate water retention or loss, and that the skin plays a role as major Na reservoir via regulation of the content of glycosaminoglycans and osmotic gradients. In the present study, we investigated whether there were electrolyte gradients in skin and where Na could be stored to be inactivated from a fluid balance viewpoint. We used two common models for salt-sensitive hypertension: high salt and a deoxycorticosterone salt diet. We found a hydration-dependent high interstitial fluid Na concentration that will contribute to the skin barrier and thus be a mechanism for limiting water loss. There was intracellular Na storage in muscle and myocardium without a concomitant increase in hydration, comprising storage that may have electromechanical consequences in salt stress.
Topics: Animals; Rats; Blood Pressure; Desoxycorticosterone; Desoxycorticosterone Acetate; Electrolytes; Glycosaminoglycans; Hypertension; Ions; Rats, Sprague-Dawley; Sodium; Sodium Chloride; Water
PubMed: 35377950
DOI: 10.1113/JP282715 -
Critical Care (London, England) Nov 2022Steroid profiles in combination with a corticotropin stimulation test provide information about steroidogenesis and its functional reserves in critically ill patients. (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
Steroid profiles in combination with a corticotropin stimulation test provide information about steroidogenesis and its functional reserves in critically ill patients.
OBJECTIVES
We investigated whether steroid profiles before and after corticotropin stimulation can predict the risk of in-hospital death in sepsis.
METHODS
An exploratory data analysis of a double blind, randomized trial in sepsis (HYPRESS [HYdrocortisone for PRevention of Septic Shock]) was performed. The trial included adult patients with sepsis who were not in shock and were randomly assigned to placebo or hydrocortisone treatment. Corticotropin tests were performed in patients prior to randomization and in healthy subjects. Cortisol and precursors of glucocorticoids (17-OH-progesterone, 11-desoxycortisol) and mineralocorticoids (11-desoxycorticosterone, corticosterone) were analyzed using the multi-analyte stable isotope dilution method (LC-MS/MS). Measurement results from healthy subjects were used to determine reference ranges, and those from placebo patients to predict in-hospital mortality.
MEASUREMENTS AND MAIN RESULTS
Corticotropin tests from 180 patients and 20 volunteers were included. Compared to healthy subjects, patients with sepsis had elevated levels of 11-desoxycorticosterone and 11-desoxycortisol, consistent with activation of both glucocorticoid and mineralocorticoid pathways. After stimulation with corticotropin, the cortisol response was subnormal in 12% and the corticosterone response in 50% of sepsis patients. In placebo patients (n = 90), a corticotropin-stimulated cortisol-to-corticosterone ratio > 32.2 predicted in-hospital mortality (AUC 0.8 CI 0.70-0.88; sensitivity 83%; and specificity 78%). This ratio also predicted risk of shock development and 90-day mortality.
CONCLUSIONS
In this exploratory analysis, we found that in sepsis mineralocorticoid steroidogenesis was more frequently impaired than glucocorticoid steroidogenesis. The corticotropin-stimulated cortisol-to-corticosterone ratio predicts the risk of in-hospital death. Trial registration Clinical trial registered with www.
CLINICALTRIALS
gov Identifier: NCT00670254. Registered 1 May 2008, https://clinicaltrials.gov/ct2/show/NCT00670254 .
Topics: Adult; Humans; Adrenocorticotropic Hormone; Hydrocortisone; Hospital Mortality; Glucocorticoids; Mineralocorticoids; Corticosterone; Cortodoxone; Chromatography, Liquid; Tandem Mass Spectrometry; Sepsis; Shock, Septic; Desoxycorticosterone
PubMed: 36345013
DOI: 10.1186/s13054-022-04224-5 -
International Journal of Molecular... Apr 2023The Na-activated Na channel (Nax) and salt-inducible kinase (SIK) are stimulated by increases in local Na concentration, affecting (Na + K)-ATPase activity. To test the...
The Na-activated Na channel (Nax) and salt-inducible kinase (SIK) are stimulated by increases in local Na concentration, affecting (Na + K)-ATPase activity. To test the hypothesis that the triad Nax/SIK/(Na + K)-ATPase contributes to kidney injury and salt-sensitive hypertension (HTN), uninephrectomized male Wistar rats (200 g; = 20) were randomly divided into 4 groups based on a salt diet (normal salt diet; NSD-0.5% NaCl-or high-salt diet; HSD-4% NaCl) and subcutaneous administration of saline (0.9% NaCl) or deoxycorticosterone acetate (DOCA, 8 mg/kg), as follows: Control (CTRL), CTRL-Salt, DOCA, and DOCA-Salt, respectively. After 28 days, the following were measured: kidney function, blood pressure, (Na + K)-ATPase and SIK1 kidney activities, and Nax and SIK1 renal expression levels. SIK isoforms in kidneys of CTRL rats were present in the glomerulus and tubular epithelia; they were not altered by HSD and/or HTN. CTRL-Salt rats remained normotensive but presented slight kidney function decay. HSD rats displayed augmentation of the Nax/SIK/(Na + K)-ATPase pathway. HTN, kidney injury, and kidney function decay were present in all DOCA rats; these were aggravated by HSD. DOCA rats presented unaltered (Na + K)-ATPase activity, diminished total SIK activity, and augmented SIK1 and Nax content in the kidney cortex. DOCA-Salt rats expressed SIK1 activity and downregulation in (Na + K)-ATPase activity in the kidney cortex despite augmented Nax content. The data of this study indicate that the (Na + K)-ATPase activity response to SIK is attenuated in rats under HSD, independent of HTN, as a mechanism contributing to kidney injury and salt-sensitive HTN.
Topics: Rats; Male; Animals; Sodium Chloride; Desoxycorticosterone Acetate; Sodium-Potassium-Exchanging ATPase; Rats, Wistar; Hypertension; Sodium; Sodium Chloride, Dietary; Blood Pressure; Kidney; Ions; Protein Serine-Threonine Kinases
PubMed: 37175599
DOI: 10.3390/ijms24097887 -
Stroke Jul 2021Hypertension is a leading risk factor for cerebrovascular disease and loss of brain health. While the brain renin-angiotensin system (RAS) contributes to hypertension,...
BACKGROUND AND PURPOSE
Hypertension is a leading risk factor for cerebrovascular disease and loss of brain health. While the brain renin-angiotensin system (RAS) contributes to hypertension, its potential impact on the local vasculature is unclear. We tested the hypothesis that activation of the brain RAS would alter the local vasculature using a modified deoxycorticosterone acetate (DOCA) model.
METHODS
C57BL/6 mice treated with DOCA (50 mg SQ; or shams) were given tap H2O and H2O with 0.9% NaCl for 1 to 3 weeks.
RESULTS
In isolated cerebral arteries and parenchymal arterioles from DOCA-treated male mice, endothelium- and nitric oxide-dependent dilation was progressively impaired, while mesenteric arteries were unaffected. In contrast, cerebral endothelial function was not significantly affected in female mice treated with DOCA. In males, mRNA expression of renal Ren1 was markedly reduced while RAS components (eg, Agt and Ace) were increased in both brain and cerebral arteries with central RAS activation. In NZ44 reporter mice expressing GFP (green fluorescent protein) driven by the angiotensin II type 1A receptor (Agtr1a) promoter, DOCA increased GFP expression ≈3-fold in cerebral arteries. Impaired endothelial responses were restored to normal by losartan, an AT1R (angiotensin II type 1 receptor) antagonist. Last, DOCA treatment produced inward remodeling of parenchymal arterioles.
CONCLUSIONS
These findings suggest activation of the central and cerebrovascular RAS impairs endothelial (nitric oxide dependent) signaling in brain through expression and activation of AT1R and sex-dependent effects. The central RAS may be a key contributor to vascular dysfunction in brain in a preclinical (low renin) model of hypertension. Because the brain RAS is also activated during aging and other diseases, a common mechanism may promote loss of endothelial and brain health despite diverse cause.
Topics: Animals; Cerebrovascular Disorders; Desoxycorticosterone Acetate; Endothelium, Vascular; Female; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nitric Oxide Synthase Type III; Receptor, Angiotensin, Type 1; Renin-Angiotensin System
PubMed: 34107734
DOI: 10.1161/STROKEAHA.121.034984 -
Function (Oxford, England) 2023Non-enzymatic activation of renin via its interaction with prorenin receptor (PRR) has been proposed as a key mechanism of local renin-angiotensin system (RAS)...
Non-enzymatic activation of renin via its interaction with prorenin receptor (PRR) has been proposed as a key mechanism of local renin-angiotensin system (RAS) activation. The presence of renin and angiotensinogen has been reported in the rostral ventrolateral medulla (RVLM). Overactivation of bulbospinal neurons in the RVLM is linked to hypertension (HTN). Previous studies have shown that the brain RAS plays a role in the pathogenesis of the deoxycorticosterone (DOCA)-salt HTN model. Thus, we hypothesized that PRR in the RVLM is involved in the local activation of the RAS, facilitating the development of DOCA-salt HTN. Selective PRR ablation targeting the RVLM (PRR mice) resulted in an unexpected sex-dependent and biphasic phenotype in DOCA-salt HTN. That is, PRR females (but not males) exhibited a significant delay in achieving maximal pressor responses during the initial stage of DOCA-salt HTN. Female PRR subsequently showed exacerbated DOCA-salt-induced pressor responses during the "maintenance" phase with a maximal peak at 13 d on DOCA-salt. This exacerbated response was associated with an increased sympathetic drive to the resistance arterioles and the kidney, exacerbated fluid and sodium intake and output in response to DOCA-salt, and induced mobilization of fluids from the intracellular to extracellular space concomitant with elevated vasopressin. Ablation of PRR suppressed genes involved in RAS activation and catecholamine synthesis in the RVLM but also induced expression of genes involved in inflammatory responses. This study illustrates complex and sex-dependent roles of PRR in the neural control of BP and hydromineral balance through autonomic and neuroendocrine systems. Graphical abstract.
Topics: Animals; Female; Mice; Blood Pressure; Desoxycorticosterone Acetate; Hypertension; Prorenin Receptor; Receptors, Cell Surface; Renin; Sodium Chloride; Vasoconstrictor Agents
PubMed: 37609445
DOI: 10.1093/function/zqad043