Cardiac fibrogenesis in magnesium deficiency: a role for circulating angiotensin II and aldosterone

2006 ◽  
Vol 291 (1) ◽  
pp. H436-H440 ◽  
Author(s):  
S. Sapna ◽  
S. K. Ranjith ◽  
K. Shivakumar
Keyword(s):  
Angiotensin Ii ◽  
Magnesium Deficiency ◽  
Cardiac Fibroblasts ◽  
Control Diet ◽  
Sprague Dawley ◽  
Adult Rats ◽  
Serum Factors ◽  
Significant Difference

Mechanisms underlying cardiac fibrogenesis in magnesium deficiency are unclear. It was reported earlier from this laboratory that serum from magnesium-deficient rats has a more pronounced stimulatory effect on cell proliferation, net collagen production, and superoxide generation in adult rat cardiac fibroblasts than serum from rats on the control diet. The profibrotic serum factors were, however, not identified. This study tested the hypothesis that circulating angiotensin II may modulate cardiac fibroblast activity in hypomagnesemic rats. Male Sprague-Dawley rats were pair-fed a magnesium-deficient (0.0008% Mg) or -sufficient (0.05%) diet for 6 days, and the effects of serum from these rats on [3H]thymidine and [3H]proline incorporation into cardiac fibroblasts from young adult rats were evaluated in the presence of losartan, an angiotensin II type 1 (AT1) receptor antagonist, and spironolactone, an aldosterone antagonist. Losartan and spironolactone markedly attenuated the stimulatory effects in vitro of serum from the magnesium-deficient and control groups, but the inhibitory effects were considerably higher in cells exposed to serum from magnesium-deficient animals. Circulating and cardiac tissue levels of angiotensin II were significantly elevated in magnesium-deficient animals (67.6% and 93.1%, respectively, vs. control). Plasma renin activity was 61.9% higher in magnesium-deficient rats, but serum angiotensin-converting enzyme activity was comparable in the two groups. Furthermore, preliminary experiments in vivo using enalapril supported a role for angiotensin II in magnesium deficiency. There was no significant difference between the groups in serum aldosterone levels. The findings suggest that circulating angiotensin II and aldosterone may stimulate fibroblast activity and contribute to a fibrogenic response in the heart in magnesium deficiency.

scholarly journals Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy

2016 ◽  
Vol 37 (6) ◽  
Author(s):  
Ritwik Datta ◽  
Trisha Bansal ◽  
Santanu Rana ◽  
Kaberi Datta ◽  
Ratul Datta Chaudhuri ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Collagen Synthesis ◽  
Cardiac Fibroblasts ◽  
Heat Shock Protein 90 ◽  
Signaling Mechanism ◽  
Content Type ◽  
Collagen Expression ◽  
Significant Difference

ABSTRACT Signal transducer and activator of transcription 3 (STAT-3)-mediated signaling in relation to upregulated collagen expression in fibroblasts during cardiac hypertrophy is well defined. Our recent findings have identified heat shock protein 90 (Hsp90) to be a critical modulator of fibrotic signaling in cardiac fibroblasts in this disease milieu. The present study was therefore intended to analyze the role of Hsp90 in the STAT-3-mediated collagen upregulation process. Our data revealed a significant difference between in vivo and in vitro results, pointing to a possible involvement of myocyte-fibroblast cross talk in this process. Cardiomyocyte-targeted knockdown of Hsp90 in rats (Rattus norvegicus) in which the renal artery was ligated showed downregulated collagen synthesis. Furthermore, the results obtained with cardiac fibroblasts conditioned with Hsp90-inhibited hypertrophied myocyte supernatant pointed toward cardiomyocytes' role in the regulation of collagen expression in fibroblasts during hypertrophy. Our study also revealed a novel signaling mechanism where myocyte-derived Hsp90 orchestrates not only p65-mediated interleukin-6 (IL-6) synthesis but also its release in exosomal vesicles. Such myocyte-derived exosomes and myocyte-secreted IL-6 are responsible in unison for the biphasic activation of STAT-3 signaling in cardiac fibroblasts that culminates in excess collagen synthesis, leading to severely compromised cardiac function during cardiac hypertrophy.

scholarly journals Angiotensin II inhibits NaCl absorption in the rat medullary thick ascending limb

2004 ◽  
Vol 287 (3) ◽  
pp. F404-F410 ◽  
Author(s):  
Nicolas Lerolle ◽  
Soline Bourgeois ◽  
Françoise Leviel ◽  
Gaëtan Lebrun ◽  
Michel Paillard ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Plasma Membranes ◽  
Inhibitory Effect ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
Experimental Conditions ◽  
Nacl Absorption ◽  
Medullary Thick Ascending Limb

NaCl reabsorption in the medullary thick ascending limb of Henle (MTALH) contributes to NaCl balance and is also responsible for the creation of medullary interstitial hypertonicity. Despite the presence of angiotensin II subtype 1 (AT1) receptors in both the luminal and the basolateral plasma membranes of MTALH cells, no information is available on the effect of angiotensin II on NaCl reabsorption in MTALH and, furthermore, on angiotensin II-dependent medullary interstitial osmolality. MTALHs from male Sprague-Dawley rats were isolated and microperfused in vitro; transepithelial net chloride absorption ( JCl) as well as transepithelial voltage ( Vte) were measured. Luminal or peritubular 10−11 and 10−10 M angiotensin II had no effect on JCl or Vte. However, 10−8 M luminal or peritubular angiotensin II reversibly decreased both JCl and Vte. The effect of both luminal and peritubular angiotensin II was prevented by the presence of losartan (10−6 M). By contrast, PD-23319, an AT2-receptor antagonist, did not alter the inhibitory effect of 10−8 M angiotensin II. Finally, no additive effect of luminal and peritubular angiotensin II was observed. We conclude that both luminal and peritubular angiotensin II inhibit NaCl absorption in the MTALH via AT1 receptors. Because of intrarenal angiotensin II synthesis, angiotensin II concentration in medullary tubular and interstitial fluids may be similar in vivo to the concentration that displays an inhibitory effect on NaCl reabsorption under the present experimental conditions.

Type II pneumocyte hypertrophy without activation of surfactant biosynthesis after partial pneumonectomy

1993 ◽  
Vol 264 (2) ◽  
pp. L153-L159 ◽  
Author(s):  
B. D. Uhal ◽  
M. D. Etter
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Tritiated Thymidine ◽  
Cell Cycle Distribution ◽  
Type Ii ◽  
Adult Rats ◽  
Type Ii Pneumocyte ◽  
Significant Difference

Hypertrophic and normotrophic type II pneumocytes were isolated from pneumonectomized adult rats by unit gravity (1 g) sedimentation or by fluorescence-activated cell sorting (FACS). In vivo or in vitro, hypertrophic cells incorporated significantly more 5-bromo-2'-deoxyuridine or tritiated thymidine into acid-insoluble material than did normotrophic cells. By FACS analysis of cell subpopulations isolated by 1 g, > 97% of normotrophic cells had G0-phase DNA content. In contrast, the cell cycle distribution of hypertrophic cells was 75% G1, 5% S, and 20% G2/M phases. Rates of incorporation of tritiated choline into total cellular phosphatidylcholine (PC) were identical in type II cells isolated from normal or pneumonectomized rats. The intracellular contents of disaturated phosphatidylcholine (DSPC) and total PC, as well as the ratio of these two lipids, were the same in hypertrophic and normotrophic cells from pneumonectomized rats and in cells isolated from normal rats. No significant difference was observed in the rate at which hypertrophic or normotrophic cells incorporated choline into DSPC. These results demonstrate that type II pneumocyte hypertrophy after pneumonectomy reflects balanced cell growth secondary to cell cycle progression in vivo. The data also indicate that epithelial cell hypertrophy after pneumonectomy, in contrast to that which develops after more acute lung injury, occurs without activation of surfactant biosynthesis or storage.

scholarly journals Ghrelin Ameliorates Angiotensin II-Induced Myocardial Fibrosis by Upregulating Peroxisome Proliferator-Activated Receptor Gamma in Young Male Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Qian Wang ◽  
Xin Sui ◽  
Rui Chen ◽  
Pei-Yong Ma ◽  
Yong-Liang Teng ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Male Rats ◽  
Peroxisome Proliferator ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Collagen Iii

Angiotensin (Ang) II contributes to the formation and development of myocardial fibrosis. Ghrelin, a gut peptide, has demonstrated beneficial effects against cardiovascular disease. In the present study, we explored the effect and related mechanism of Ghrelin on myocardial fibrosis in Ang II-infused rats. Adult Sprague-Dawley (SD) rats were divided into 6 groups: Control, Ang II (200ng/kg/min, microinfusion), Ang II+Ghrelin (100μg/kg, subcutaneously twice daily), Ang II+Ghrelin+GW9662 (a specific PPAR-γinhibitor, 1 mg/kg/d, orally), Ang II+GW9662, and Ghrelin for 4 wks. In vitro, adult rat cardiac fibroblasts (CFs) were pretreated with or without Ghrelin, Ghrelin+GW9662, or anti-Transforming growth factor (TGF)-β1 antibody and then stimulated with or without Ang II (100 nmol/L) for 24 h. Ang II infusion significantly increased myocardial fibrosis, expression of collagen I, collagen III, and TGF-β1, as well as TGF-β1 downstream proteins p-Smad2, p-Smad3, TRAF6, and p-TAK1 (all p<0.05). Ghrelin attenuated these effects. Similar results were seen in Ang II-stimulated rat cardiac fibroblasts in vitro. In addition, Ghrelin upregulated PPAR-γexpressionin vivoandin vitro, and treatment with GW9662 counteracted the effects of Ghrelin. In conclusion, Ghrelin ameliorated Ang II-induced myocardial fibrosis by upregulating PPAR-γand in turn inhibiting TGF-β1signaling.

scholarly journals In Vivo Toxicity and In Vitro Solubility Assessment of Pre-Treated Struvite as a Potential Alternative Phosphorus Source in Animal Feed

Animals ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 785 ◽  
Author(s):  
Soomin Shim ◽  
Seunggun Won ◽  
Arif Reza ◽  
Seungsoo Kim ◽  
Sungil Ahn ◽  
...  
Keyword(s):  
Animal Feed ◽  
Histopathological Examination ◽  
Sprague Dawley ◽  
Alternative Source ◽  
Lung Weight ◽  
In Vivo Toxicity ◽  
Significant Difference ◽  
Potential Alternative

Apart from using as fertilizer for plants, the application of struvite may be expanded to animal feed industries through proper pre-treatment. This study aimed to investigate the safety and efficacy of using pre-treated struvite (microwave irradiated struvite (MS) and incinerated struvite (IS)) in animal feeds. For safety assessment, an in vivo toxicity experiment using thirty female Sprague Dawley rats (average body weight (BW) of 200 ± 10 g) was conducted. The rats were randomly divided into five groups, including a control. Based on the BW, MS and IS were applied daily by oral administration with 1 and 10 mg kg−1-BW (MS1 and MS10; IS1 and IS10) using dimethyl sulfoxide (DMSO) as a vehicle. A series of jar tests were conducted for four hours to check the solubility of the MS and IS at different pH (pH 2, 4, 5, 6, and 7) and compared to a commercial P source (monocalcium phosphate, MCP, control). The toxicity experiment results showed no significant differences among the treatments in BW and organ (liver, kidney, heart, and lung) weight of rats (p > 0.05). There were no adverse effects on blood parameters and the histopathological examination showed no inflammation in the organ tissues in MS and IS treated groups compared to the control. In an in vitro solubility test, no significant difference was observed in ortho-phosphate (O-P) solubility from the MCP and MS at pH 2 and 4 (p > 0.05), while O-P solubility from MS at pH 5 to 7 was higher than MCP and found to be significantly different (p < 0.05). O-P solubility from IS was the lowest among the treatments and significantly different from MCP and MS in all the experiments (p < 0.05). The results of this study not only suggest that the struvite pre-treated as MS could be a potential alternative source of P in animal feed but also motivate further studies with more stringent designs to better examine the potential of struvite application in diverse fields.

scholarly journals Glutamine gluconeogenesis in the small intestine of 72 h-fasted adult rats is undetectable

2006 ◽  
Vol 401 (2) ◽  
pp. 465-473 ◽  
Author(s):  
Guy Martin ◽  
Bernard Ferrier ◽  
Agnès Conjard ◽  
Mireille Martin ◽  
Rémi Nazaret ◽  
...  
Keyword(s):  
Small Intestine ◽  
Glucose Production ◽  
Sprague Dawley ◽  
Adult Rats ◽  
Concentration Difference ◽  
Adult Rat ◽  
Nutrition And Diabetes ◽  
Glucose Synthesis

Recent reports have indicated that 48–72 h of fasting, Type 1 diabetes and high-protein feeding induce gluconeogenesis in the small intestine of adult rats in vivo. Since this would (i) represent a dramatic revision of the prevailing view that only the liver and the kidneys are gluconeogenic and (ii) have major consequences in the metabolism, nutrition and diabetes fields, we have thoroughly re-examined this question in the situation reported to induce the highest rate of gluconeogenesis. For this, metabolically viable small intestinal segments from 72 h-fasted adult rats were incubated with [3-13C]glutamine as substrate. After incubation, substrate utilization and product accumulation were measured by enzymatic and NMR spectroscopic methods. Although the segments utilized [13C]glutamine at high rates and accumulated 13C-labelled products linearly for 30 min in vitro, no substantial glucose synthesis could be detected. This was not due to the re-utilization of [13C]glucose initially synthesized from [13C]glutamine. Arteriovenous metabolite concentration difference measurements across the portal vein-drained viscera of 72 h-fasted Wistar and Sprague–Dawley rats clearly indicated that glutamine, the main if not the only gluconeogenic precursor taken up, could not give rise to detectable glucose production in vivo. Therefore we challenge the view that the small intestine of the adult rat is a gluconeogenic organ.

scholarly journals Magnolol Attenuates Right Ventricular Hypertrophy and Fibrosis in Hypoxia-Induced Pulmonary Arterial Hypertensive Rats Through Inhibition of the JAK2/STAT3 Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Minyi Fu ◽  
Fangmei Luo ◽  
Eli Wang ◽  
Yueping Jiang ◽  
Shao Liu ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Signaling Pathway ◽  
Cardiac Fibroblasts ◽  
Sprague Dawley ◽  
Clinical Value ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Pulmonary Arterial

Right ventricular (RV) remodeling is one of the essential pathological features in pulmonary arterial hypertension (PAH). RV hypertrophy or fibrosis are the leading causes of RV remodeling. Magnolol (6, 6′, 7, 12-tetramethoxy-2,2′-dimethyl-1-β-berbaman, C18H18O2) is a compound isolated from Magnolia Officinalis. It possesses multiple pharmacological activities, such as anti-oxidation and anti-inflammation. This study aims to evaluate the effects and underlying mechanisms of magnolol on RV remodeling in hypoxia-induced PAH. In vivo, male Sprague Dawley rats were exposed to 10% O2 for 4 weeks to establish an RV remodeling model, which showed hypertrophic and fibrotic features (increases of Fulton index, cellular size, hypertrophic and fibrotic marker expression), accompanied by an elevation in phosphorylation levels of JAK2 and STAT3; these changes were attenuated by treating with magnolol. In vitro, the cultured H9c2 cells or cardiac fibroblasts were exposed to 3% O2 for 48 h to induce hypertrophy or fibrosis, which showed hypertrophic (increases in cellular size as well as the expression of ANP and BNP) or fibrotic features (increases in the expression of collagen Ⅰ, collagen Ⅲ, and α-SMA). Administration of magnolol and TG-101348 or JSI-124 (both JAK2 selective inhibitors) could prevent myocardial hypertrophy and fibrosis, accompanied by the decrease in the phosphorylation level of JAK2 and STAT3. Based on these observations, we conclude that magnolol can attenuate RV hypertrophy and fibrosis in hypoxia-induced PAH rats through a mechanism involving inhibition of the JAK2/STAT3 signaling pathway. Magnolol may possess the potential clinical value for PAH therapy.

Abstract 640: Overexpression of Vasohibin-2 Exacerbates Development of Angiotensin II-Induced Thoracic Aortic Aneurysms Independent of VeEGF

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Michihiro Okuyama ◽  
Haruhito A Uchida ◽  
Ryoko Umebayashi ◽  
Yuki Kakio ◽  
Hidemi Takeuchi ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Expression ◽  
Aortic Arch ◽  
Gelatin Zymography ◽  
Annexin V ◽  
Aortic Aneurysms ◽  
Tunel Staining ◽  
Significant Difference

Objective: Chronic angiotensin II (AngII) infusion promotes both thoracic (TAAs) and abdominal aortic aneurysms (AAAs) in mice. Vasohibin-2 (VASH2) is known to cause angiogenesis at the sprouting front of neovascularization. The purpose of this study was to examine whether VASH2 influenced AngII-induced TAAs. Methods: Male C57BL/6J mice (10-week-old) were injected with VASH2 or LacZ expressing adenovirus (Ad; 7.5 x 10 9 vp/100 μL) via tail vein at 2 week intervals. One week after the first injection, subcutaneous infusion of either AngII (1,000 ng/kg/min) or saline by mini osmotic pumps was started for 3 weeks. Consequently, mice were divided into 4 groups: AngII + Ad VASH2 (n=22), AngII + Ad LacZ (n=21), saline + Ad VASH2 (n=10), saline + Ad LacZ (n=8). Next, in order to examine whether VASH2 affected TAAs via VEGF regulation, bevacizumab was intraperitoneally administrated into mice; AngII + Ad VASH2 + saline (n=15), AngII + Ad VASH2 + bevacizumab (n=15). TAAs were evaluated in all mice by en face method. Third, human aortic smooth muscle cells (hSMCs) were infected with Ad VASH2 or Ad LacZ, stimulated with or without AngII to evaluate further mechanism. Result: Intima area of aortic arch was significantly larger in AngII + Ad VASH2 group than in AngII + Ad LacZ group (19.78 ± 0.40 mm 3 vs 17.74 ± 0.44 mm 3 , P < 0.001). Gelatin zymography demonstrated that AngII upregulated latent MMP-2 expression, and activated MMP-2 most prominently in AngII + VASH2 group. Protein expression of p21 and p53 in thoracic aortas was enhanced in AngII + VASH2 group. Positive TUNEL staining was observed in thoracic aortic wall of AngII + VASH2 group. No significant difference in intima area of aortic arch between AngII + Ad VASH2 + saline group and AngII + Ad VASH2 + bevacizumab group. In vitro, the same results were observed regarding protein expression of p21 and p53, and TUNEL staining. In addition, Annexin-V staining was detected only in AngII + VASH2 group. Conclusion: Overexpression of VASH2 accelerated development of AngII-induced TAAs in vivo. VASH2-induced cell apoptosis may influence AngII-induced TAA formation independent of VEGF.

Luminal calcium concentration controls intestinal calcium absorption by modification of intestinal alkaline phosphatase activity

2011 ◽  
Vol 108 (2) ◽  
pp. 229-233 ◽  
Author(s):  
Lucas R. Brun ◽  
María L. Brance ◽  
Alfredo Rigalli
Keyword(s):  
Alkaline Phosphatase ◽  
Calcium Absorption ◽  
Sprague Dawley ◽  
Intestinal Alkaline Phosphatase ◽  
Significant Difference ◽  
Luminal Calcium ◽  
Duodenal Lumen ◽  
Over Time

Intestinal alkaline phosphatase (IAP) is a brush-border phosphomonoesterase. Its location suggests an involvement in the uptake of nutrients, but its role has not yet been defined. IAP expression parallels that of other proteins involved in Ca absorption under vitamin D stimulation. Experiments carried out in vitro with purified IAP have demonstrated an interaction between Ca and IAP. The gut is prepared to face different levels of Ca intake over time, but high Ca intake in a situation of a low-Ca diet over time would cause excessive entry of Ca into the enterocytes. The presence of a mechanism to block Ca entry and to avoid possible adverse effects is thus predictable. Thus, in the present study, Sprague–Dawley rats were fed with different amounts of Ca in the diet (0·2, 1 and 2 g%), and the percentage of Ca absorption (%Ca) in the presence and absence of l-phenylalanine (Phe) was calculated. The presence of Phe caused a significant increase in %Ca (52·3 (sem 6·5) % in the presence of Phe v. 31·1 (sem 8·9) % in the absence of Phe, regardless of the amount of Ca intake; paired t test, P = 0·02). When data were analysed with respect to Ca intake, a significant difference was found only in the group with low Ca intake (paired t test, P = 0·03). Additionally, IAP activity increased significantly (ANOVA, P < 0·05) as Ca concentrations increased in the duodenal lumen. The present study provides in vivo evidence that luminal Ca concentration increases the activity of IAP and simultaneously decreases %Ca, acting as a minute-to-minute regulatory mechanism of Ca entry.

Preparation of cultured astrocytes for x-ray microanalysis

1989 ◽  
Vol 47 ◽  
pp. 988-989
Author(s):  
N.K.R. Smith ◽  
K.E. Hunter ◽  
P. Mobley ◽  
L.P. Felpel
Keyword(s):  
Cultured Cells ◽  
Elemental Content ◽  
Elemental Distribution ◽  
Sprague Dawley ◽  
X Ray ◽  
Cultured Astrocytes ◽  
Freeze Dried ◽  
Ultimate Objective

Electron probe energy dispersive x-ray microanalysis (XRMA) offers a powerful tool for the determination of intracellular elemental content of biological tissue. However, preparation of the tissue specimen , particularly excitable central nervous system (CNS) tissue , for XRMA is rather difficult, as dissection of a sample from the intact organism frequently results in artefacts in elemental distribution. To circumvent the problems inherent in the in vivo preparation, we turned to an in vitro preparation of astrocytes grown in tissue culture. However, preparations of in vitro samples offer a new and unique set of problems. Generally, cultured cells, growing in monolayer, must be harvested by either mechanical or enzymatic procedures, resulting in variable degrees of damage to the cells and compromised intracel1ular elemental distribution. The ultimate objective is to process and analyze unperturbed cells. With the objective of sparing others from some of the same efforts, we are reporting the considerable difficulties we have encountered in attempting to prepare astrocytes for XRMA.Tissue cultures of astrocytes from newborn C57 mice or Sprague Dawley rats were prepared and cultured by standard techniques, usually in T25 flasks, except as noted differently on Cytodex beads or on gelatin. After different preparative procedures, all samples were frozen on brass pins in liquid propane, stored in liquid nitrogen, cryosectioned (0.1 μm), freeze dried, and microanalyzed as previously reported.

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