Receptor signaling and neutral endopeptidase are involved in the resistance of C-type natriuretic peptide to human mesangial proliferation and collagen-IV expression

2018 ◽  
Vol 66 (5) ◽  
pp. 1.1-9 ◽  
Author(s):  
Huang Huang Luo ◽  
Cheng Wu ◽  
Peng Hu ◽  
Yang Fang Wu ◽  
Dong Dong Zhang ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Mesangial Cells ◽  
Neutral Endopeptidase ◽  
Collagen Iv ◽  
Guanosine Monophosphate ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Receptor Signaling ◽  
Signal Molecule ◽  
Mesangial Proliferation

C-type natriuretic peptide (CNP) is regarded as a local, paracrine hormone to regulate vascular tone and cell proliferation. Although several in vivo studies have documented that CNP exerts the inhibitory effects on mesangial cells (MCs) proliferation and collagen production, a limited number of studies exist about the resistance of CNP to MCs proliferation in vitro. Besides, whether its receptor signaling and neutral endopeptidase (NEP) are involved remains unclear. In the present study, human MCs were incubated in serum-containing medium in the absence or presence of CNP (0, 10 and 100 pM) for 24, 48 and 72 hours, respectively. CNP administration significantly suppresses MCs proliferation and collagen-IV (Col-IV) expression in a time-dependent and dose-dependent manner. As a down-stream signal molecule of CNP activation, the expressions of natriuretic peptide receptor (NPR)-B, cyclic guanosine monophosphate-dependent protein kinases II and NPR-C were obviously augmented, whereas NEP expression was significantly decreased after CNP treatment. In conclusion, receptor signaling and NEP are involved in the resistance of CNP to human mesangial proliferation and Col-IV expression.

Evaluation of SQ 28 603, an inhibitor of neutral endopeptidase, in conscious monkeys

1991 ◽  
Vol 69 (10) ◽  
pp. 1609-1617 ◽  
Author(s):  
Andrea A. Seymour ◽  
Benoni Abboa-Offei ◽  
Magdi M. Asaad ◽  
W. Lynn Rogers
Keyword(s):  
Blood Pressure ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Sodium Excretion ◽  
Neutral Endopeptidase ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Excretory Function ◽  
Plasma Atrial Natriuretic Peptide ◽  
Atrial Natriuretic

The potent neutral endopeptidase inhibitor SQ 28 603 (N-(2-(mercaptomethyl)-1-oxo-3-phenylpropyl)-β-alanine) significantly increased excretion of sodium from 4.9 ± 2.3 to 14.3 ± 2.1 μequiv./min and cyclic 3′,5′-guanosine monophosphate from 118 ± 13 to 179 ± 18 pmol/min after intravenous administration of 300 μmol/kg (~80 mg/kg) in conscious female cynomolgus monkeys. SQ 28 603 did not change blood pressure or plasma atrial natriuretic peptide concentrations in the normal monkeys. In contrast, 1-h infusions of 3, 10, or 30 pmol∙kg−1∙min−1 of human atrial natriuretic peptide lowered blood pressure by −3 ± 4, −9 ± 4, and −27 ± 3 mmHg (1 mmHg = 133.322 Pa), increased cyclic guanosine monophosphate excretion from 78 ± 11 to 90 ± 6, 216 ± 33, and 531 ± 41 pmol/min, and raised plasma atrial natriuretic peptide from 7.2 ± 0.7 to 21 ± 4, 62 ± 12, and 192 ± 35 fmol/mL without affecting sodium excretion. In monkeys receiving 10 pmol∙kg−1∙min−1 of atrial natriuretic peptide, 300 μmol/kg of SQ 28 603 reduced mean arterial pressure by −13 ± 5 mmHg and increased sodium excretion from 6.6 ± 3.2 to 31.3 ± 6.0 μequiv./min, cyclic guanosine monophosphate excretion from 342 ± 68 to 1144 ± 418 pmol/min, and plasma atrial natriuretic peptide from 124 ± 8 to 262 ± 52 fmol/mL. In conclusion, SQ 28 603 stimulated renal excretory function in conscious monkeys, presumably by preventing the degradation of atrial natriuretic peptide by neutral endopeptidase.Key words: atrial natriuretic peptide, neutral endopeptidase, natriuresis, cyclic guanosine monophosphate.

Rapamycin at subimmunosuppressive levels inhibits mesangial cell proliferation and extracellular matrix production

2007 ◽  
Vol 292 (1) ◽  
pp. F76-F81 ◽  
Author(s):  
Helen R. Lock ◽  
Steven H. Sacks ◽  
Michael G. Robson
Keyword(s):  
Cell Proliferation ◽  
Dna Synthesis ◽  
Mechanism Of Action ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Primary Cultures ◽  
Cell Number ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Mesangial Cell Proliferation

In view of its proven antiproliferative effects, rapamycin offers potential in the treatment of mesangioproliferative disease. Previous data have shown an effect of rapamycin on mesangial cell proliferation at high doses and have not explored the mechanism of action. Therefore, we explored the effects and mechanism of action of low levels of rapamycin on mesangial cell proliferation. Primary cultures of mouse mesangial cells were grown in medium containing serum with differing concentrations of rapamycin. A rapamycin concentration of 0.1 ng/ml caused a decrease in cell number and DNA synthesis with no effect on apoptosis. Type IV collagen protein production was inhibited at 0.01 ng/ml rapamycin, although gene expression was unaffected. P70S6K phosphorylation was inhibited in parallel with the effects on cell number and DNA synthesis in a dose-dependent manner, but no effect was seen at 0.01 ng/ml rapamycin. These data show an effect on mesangial cell proliferation and p70S6 kinase phosphorylation of 0.1 ng/ml rapamycin and an effect on collagen IV production of 0.01 ng/ml rapamycin. We suggest that further in vivo studies should explore the potential for low-dose rapamycin in the treatment of mesangioproliferative glomerulonephritis.

scholarly journals High glucose inhibits nitric oxide production in cultured rat mesangial cells.

1997 ◽  
Vol 8 (8) ◽  
pp. 1276-1282
Author(s):  
H Trachtman ◽  
S Futterweit ◽  
D L Crimmins
Keyword(s):  
Nitric Oxide ◽  
High Glucose ◽  
Glucose Concentration ◽  
Transforming Growth Factor ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Guanosine Monophosphate ◽  
Time Dependent ◽  
No Production ◽  
Dependent Manner

Hyperglycemia directly contributes to the development of diabetic nephropathy. A high-serum glucose concentration alters intraglomerular hemodynamics and promotes deposition of extracellular matrix in the kidney. Nitric oxide (NO) is a short-lived messenger molecule that participates in the regulation of renal blood flow, GFR, and mesangial matrix accumulation. Therefore, in this study it was tested whether high glucose directly modulates NO synthesis by rat mesangial cells in vitro by measuring the accumulation of nitrite, the stable metabolite of NO, in the incubation media. Raising the external glucose concentration to 33.3 mM for 24 to 72 h reduced nitrite levels in cell supernatants in a time-dependent manner to a nadir of 14 +/- 3% of the amount in normal glucose media (5.6 mM) (P < 0.01). The decline in NO synthesis in high glucose media was paralleled by decreased cyclic guanosine monophosphate generation; however, there was no alteration in rat mesangial cell expression of inducible NO synthase protein. The suppressive effect of high glucose on NO production by mesangial cells was not modified by inhibition of protein kinase C (H-7), the addition of antioxidants (vitamin E or superoxide dismutase), or a pan-specific anti-transforming growth factor-beta antibody. An elevated ambient glucose caused a time-dependent reduction in mesangial cell L-arginine content. Addition of L-arginine (10 to 20 mM) to external media partially reversed the inhibitory effect of high glucose on mesangial cell NO production in a dose-dependent manner. The highest dose of L-arginine (20 mM) increased mesangial cell L-arginine content to comparable levels in normal and high glucose media. These results indicate that high glucose causes depletion of L-arginine in mesangial cells and compromises NO synthesis. Limitation in the metabolic precursor and other, as yet unidentified, factors act to reduce NO production by mesangial cells in the presence of an elevated ambient glucose level, a change that may play a role in the development of diabetic glomerulosclerosis.

scholarly journals Mycophenolic acid: a new approach to the therapy of experimental mesangial proliferative glomerulonephritis.

1998 ◽  
Vol 9 (11) ◽  
pp. 2055-2066 ◽  
Author(s):  
R Ziswiler ◽  
K Steinmann-Niggli ◽  
A Kappeler ◽  
C Daniel ◽  
H P Marti
Keyword(s):  
Mycophenolic Acid ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Smooth Muscle Actin ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
New Approach ◽  
Matrix Deposition ◽  
Renal Histology

Mycophenolate mofetil (MMF) represents a powerful immunosuppressant in organ transplantation. The aim of this study was to determine the anti-inflammatory effects of MMF on mesangial cells. Cultured rat mesangial cells were exposed to mycophenolic acid (MPA) in concentrations of 0.1 to 10 microM. MPA inhibited the proliferation of these cells in a dose-dependent manner. A maximum of 98% inhibition was obtained by a 2-d exposure of mesangial cells to > or =5 microM MPA. As expected, the addition of > or =75 microM guanosine prevented the antiproliferative effect of MPA completely. Subsequently, in vivo studies were performed in the anti-Thy1.1 nephritis model. Sixty-six male Wistar rats were investigated: healthy rats (n = 15), treated healthy rats (n = 6), nephritic rats (n = 15), and treated nephritic rats (n = 30). MMF therapy (40 mg/kg body wt per d) of nephritic animals was initiated 2 d before (n = 3) and 6 h (n = 15) or 2 d (n = 12) after induction of nephritis. Renal histology was analyzed at days +6 and +9 after initiation of disease. Therapy of nephritic rats by MMF resulted in a significant amelioration of glomerular histology, assessed by glomerular cellularity, synthesis of alpha-smooth muscle actin, extracellular matrix deposition, and glomerular hypertrophy. Proteinuria, expressed as areas under the curve of protein/creatinine ratios versus time, showed a clear tendency toward a reduction by MMF therapy. Healthy control rats were not negatively affected by exposure to MMF. In summary, this study shows that mesangial cell proliferation can be significantly inhibited by MPA in vitro and in vivo. MMF represents a new approach to the therapy of experimental mesangial cell-mediated forms of glomerulonephritis.

Natriuretic Peptides Regulate the Expression of Tissue Factor and PAI-1 in Endothelial Cells

1999 ◽  
Vol 82 (11) ◽  
pp. 1497-1503 ◽  
Author(s):  
Hajime Tsuji ◽  
Hiromi Nishimura ◽  
Haruchika Masuda ◽  
Yasushi Kunieda ◽  
Hidehiko Kawano ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tissue Factor ◽  
Plasminogen Activator ◽  
Natriuretic Peptide ◽  
Culture Media ◽  
Tissue Type ◽  
Dependent Manner ◽  
Ang Ii ◽  
Plasminogen Activator Inhibitor 1 ◽  
Pai 1

SummaryIn the present study, we demonstrate that brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) interact with angiotensin II (Ang II) in regulative blood coagulation and fibrinolysis by suppressing the expressions of both tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) induced by Ang II. The expressions of TF and PAI-1 mRNA were analyzed by northern blotting methods, and the activities of TF on the surface of rat aortic endothelial cells (RAECs) and PAI-1 in the culture media were respectively measured by chromogenic assay.Both BNP and CNP suppressed the expressions of TF and PAI-1 mRNA induced by Ang II in a time- and concentration-dependent manner via cGMP cascade, which suppressions were accompanied by respective decrease in activities of TF and PAI-1. However, neither the expression of tissue factor pathway inhibitor (TFPI) nor tissue-type plasminogen activator (TPA) mRNA was affected by the treatment of BNP and CNP.

Polydatin Attenuates Carbachol-induced Contraction of Guinea Pig Gallbladder

2019 ◽  
Vol 18 (1) ◽  
pp. 34-38
Author(s):  
Chen Lei ◽  
Pan Xiang ◽  
Shen Yonggang ◽  
Song Kai ◽  
Zhong Xingguo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Guinea Pig ◽  
Smooth Muscles ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Dependent Manner ◽  
Underlying Mechanisms ◽  
Dose Dependent

The aim of this study was to determine whether polydatin, a glucoside of resveratrol isolated from the root of Polygonum cuspidatum, warranted development as a potential therapeutic for ameliorating the pain originating from gallbladder spasm disorders and the underlying mechanisms. Guinea pig gallbladder smooth muscles were treated with polydatin and specific inhibitors to explore the mechanisms underpinning polydatin-induced relaxation of carbachol-precontracted guinea pig gallbladder. Our results shown that polydatin relaxed carbachol-induced contraction in a dose-dependent manner through the nitric oxide/cyclic guanosine monophosphate/protein kinase G and the cyclic adenosine monophosphate/protein kinase A signaling pathways as well as the myosin light chain kinase and potassium channels. Our findings suggested that there was value in further exploring the potential therapeutic use of polydatin in gallbladder spasm disorders.

Platelet-activating factor and the kidney

1986 ◽  
Vol 251 (1) ◽  
pp. F1-F11 ◽  
Author(s):  
D. Schlondorff ◽  
R. Neuwirth
Keyword(s):  
De Novo ◽  
Mesangial Cells ◽  
Biological Activities ◽  
Platelet Activating Factor ◽  
Calcium Ionophore ◽  
Initial Step ◽  
Renal Physiology ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Isolated Kidney

Platelet-activating factor (PAF) represents a group of phospholipids with the basic structure of 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine. A number of different cells are capable of producing PAF in response to various stimuli. The initial step of PAF formation is activation of phospholipase A2 in a calcium-dependent manner, yielding lyso-PAF. During this step arachidonic acid is also released and can be converted to its respective cyclooxygenase and lipoxygenase products. The lyso-PAF generated is then acetylated in position 2 of the glycerol backbone by a coenzyme A (CoA)-dependent acetyltransferase. An additional pathway may exist whereby PAF is generated de novo from 1-alkyl-2-acetyl-sn-glycerol by phosphocholine transferase. PAF inactivation in cells and blood is by specific acetylhydrolases. PAF exhibits a variety of biological activities including platelet and leukocyte aggregation and activation, increased vascular permeability, respiratory distress, decreased cardiac output, and hypotension. In the kidney PAF can produce decreases in blood flow, glomerular filtration, and fluid and electrolyte excretion. Intrarenal artery injection of PAF may also result in glomerular accumulation of platelets and leukocytes and mild proteinuria. PAF increases prostaglandin formation in the isolated kidney and in cultured glomerular mesangial cells. PAF also causes contraction of mesangial cells. Upon stimulation with calcium ionophore the isolated kidney, isolated glomeruli and medullary cells, and cultured mesangial cells are capable of producing PAF. The potential role for PAF in renal physiology and pathophysiology requires further investigation that may be complicated by 1) the multiple interactions of PAF, prostaglandins, and leukotrienes and 2) the autocoid nature of PAF, which may restrict its action to its site of generation.

scholarly journals ANP and BNP Exert Anti-Inflammatory Action via NPR-1/cGMP Axis by Interfering with Canonical, Non-Canonical, and Alternative Routes of Inflammasome Activation in Human THP1 Cells

2020 ◽  
Vol 22 (1) ◽  
pp. 24
Author(s):  
Letizia Mezzasoma ◽  
Vincenzo Nicola Talesa ◽  
Rita Romani ◽  
Ilaria Bellezza
Keyword(s):  
Natriuretic Peptide ◽  
Specific Inhibitor ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Caspase 8 ◽  
Inflammasome Activation ◽  
Intracellular Cgmp ◽  
Dependent Protein ◽  
Anti Inflammatory ◽  
Alternative Routes

Dysregulated inflammasome activation and interleukin (IL)-1β production are associated with several inflammatory disorders. Three different routes can lead to inflammasome activation: a canonical two-step, a non-canonical Caspase-4/5- and Gasdermin D-dependent, and an alternative Caspase-8-mediated pathway. Natriuretic Peptides (NPs), Atrial Natriuretic Peptide (ANP) and B-type Natriuretic Peptide (BNP), binding to Natriuretic Peptide Receptor-1 (NPR-1), signal by increasing cGMP (cyclic guanosine monophosphate) levels that, in turn, stimulate cGMP-dependent protein kinase-I (PKG-I). We previously demonstrated that, by counteracting inflammasome activation, NPs inhibit IL-1β secretion. Here we aimed to decipher the molecular mechanism underlying NPs effects on THP-1 cells stimulated with lipopolysaccharide (LPS) + ATP. Involvement of cGMP and PKG-I were assessed pre-treating THP-1 cells with the membrane-permeable analogue, 8-Br-cGMP, and the specific inhibitor KT-5823, respectively. We found that NPs, by activating NPR-1/cGMP/PKG-I axis, lead to phosphorylation of NLRP3 at Ser295 and to inflammasome platform disassembly. Moreover, by increasing intracellular cGMP levels and activating phosphodiesterases, NPs interfere with both Gasdermin D and Caspase-8 cleavage, indicating that they disturb non-canonical and alternative routes of inflammasome activation. These results showed that ANP and BNP anti-inflammatory and immunomodulatory actions may involve the inhibition of all the known routes of inflammasome activation. Thus, NPs might be proposed for the treatment of the plethora of diseases caused by a dysregulated inflammasome activation.

scholarly journals Modulatory Effects of Osthole on Lipopolysaccharides-Induced Inflammation in Caco-2 Cell Monolayer and Co-Cultures with THP-1 and THP-1-Derived Macrophages

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 123
Author(s):  
Natalia K. Kordulewska ◽  
Justyna Topa ◽  
Małgorzata Tańska ◽  
Anna Cieślińska ◽  
Ewa Fiedorowicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Reaction ◽  
Wide Spectrum ◽  
Cell Monolayer ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Tnf Α

Lipopolysaccharydes (LPS) are responsible for the intestinal inflammatory reaction, as they may disrupt tight junctions and induce cytokines (CKs) secretion. Osthole has a wide spectrum of pharmacological effects, thus its anti-inflammatory potential in the LPS-treated Caco-2 cell line as well as in Caco-2/THP-1 and Caco-2/macrophages co-cultures was investigated. In brief, Caco-2 cells and co-cultures were incubated with LPS to induce an inflammatory reaction, after which osthole (150–450 ng/mL) was applied to reduce this effect. After 24 h, the level of secreted CKs and changes in gene expression were examined. LPS significantly increased the levels of IL-1β, -6, -8, and TNF-α, while osthole reduced this effect in a concentration-dependent manner, with the most significant decrease when a 450 ng/mL dose was applied (p < 0.0001). A similar trend was observed in changes in gene expression, with the significant osthole efficiency at a concentration of 450 ng/μL for IL1R1 and COX-2 (p < 0.01) and 300 ng/μL for NF-κB (p < 0.001). Osthole increased Caco-2 monolayer permeability, thus if it would ever be considered as a potential drug for minimizing intestinal inflammatory symptoms, its safety should be confirmed in extended in vitro and in vivo studies.

scholarly journals Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 386
Author(s):  
Tung-Hu Tsai ◽  
Yu-Jen Chen ◽  
Li-Ying Wang ◽  
Chen-Hsi Hsieh
Keyword(s):  
Stereotactic Body Radiation Therapy ◽  
In Vivo Studies ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Hep G2 ◽  
Time Curve ◽  
Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

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