Losartan inhibits STAT1 activation and protects human glomerular mesangial cells from angiotensin II induced premature senescence

2012 ◽  
Vol 90 (1) ◽  
pp. 89-98 ◽  
Author(s):  
Sumin Jiao ◽  
Xiaoyu Zheng ◽  
Xue Yang ◽  
Jin Zhang ◽  
Lining Wang
Keyword(s):  
Angiotensin Ii ◽  
Mesangial Cells ◽  
Morphological Changes ◽  
Positive Staining ◽  
Ang Ii ◽  
Glomerular Mesangial Cells ◽  
Cycle Arrest ◽  
Age Related ◽  
Elevated Expression ◽  
Human Glomerular Mesangial Cells

Human glomerular mesangial cells (HMCs) have a finite lifespan, and eventually enter irreversible growth arrest known as cellular senescence, which is thought to contribute to kidney ageing and age-related kidney disorders, such as chronic kidney disease. The signal transducer and activator of transcription 1 (STAT1) is a latent transcription factor involved in a variety of signal transduction pathways, including cell proliferation, apoptosis, and differentiation, but whether it could regulate HMC senescence still remains to be explored. In our study, the induction of angiotensin II (Ang II)-accelerated HMC senescence, as judged by increased senescence-associated β-galactosidase (SA-β-gal)-positive staining cells, morphological changes, and G0/G1 cell cycle arrest. STAT1 activity and the expression of p53 and p21Cip1 were increased after Ang II treatment. STAT1 knockdown using RNA interference significantly inhibited the progression of HMC senescence and decreased the elevated expression of p53 and p21Cip1. Pretreating HMCs with Ang II receptor blocker losartan also inhibited the progression of HMC senescence and STAT1 activity. Our results indicate that STAT1 is implicated in the mediation of Ang II-induced HMC senescence through p53/ p21Cip1 pathway, and that losartan could attenuate HMC senescence by regulating STAT1. The antioxidant N-acetyl-L-cysteine reduced ROS production and STAT1 activity induced by Ang II, indicating that Ang II uses ROS as a second messenger to regulate STAT1 activity.

Angiotensin II receptor subtypes determine induced NO production in rat glomerular mesangial cells

2000 ◽  
Vol 279 (6) ◽  
pp. F1092-F1100 ◽  
Author(s):  
Jörg Schwöbel ◽  
Tina Fischer ◽  
Bettina Lanz ◽  
Markus Mohaupt
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Mesangial Cells ◽  
Receptor Expression ◽  
Receptor Subtypes ◽  
No Production ◽  
Ang Ii ◽  
Glomerular Mesangial Cells ◽  
Nitrite Production ◽  
The Impact

Angiotensin II (ANG II) and nitric oxide (NO) have contrasting vascular effects, yet both sustain inflammatory responses. We investigated the impact of ANG II on lipopolysaccharide (LPS)/interferon-γ (IFN)-induced NO production in cultured rat mesangial cells (MCs). LPS/IFN-induced nitrite production, the inducible form of nitric oxide synthase (NOS-2) mRNA, and protein expression were dose dependently inhibited by ANG II on coincubation, which was abolished on ANG II type 2 (AT2) receptor blockade by PD-123319. Homology-based RT-PCR verified the presence of AT1A, AT1B, and AT2 receptors. To shift the AT receptor expression toward the type 1 receptor, two sets of experiments were performed: LPS/IFN preincubation for 24 h was followed by 8-h coincubation with ANG II; or during 24-h coincubation of LPS/IFN and ANG II, dexamethasone was added for the last 6-h period. Both led to an amplified overall expression of NOS-2 protein and NO production that was inhibitable by actinomycin D in the first setup. Induced NO production was enhanced via the AT1 receptor; however, it was diminished via the AT2 receptor. In conclusion, induced NO production is negatively controlled by the AT2, whereas AT1 receptor stimulation enhanced NO synthesis in MCs. The overall NO availability depended on the onset of the inflammatory stimuli with respect to ANG II exposure and the available AT receptors.

Characterization of angiotensin II receptor subtypes in human glomeruli and mesangial cells

1992 ◽  
Vol 262 (3) ◽  
pp. F432-F441 ◽  
Author(s):  
D. Chansel ◽  
S. Czekalski ◽  
P. Pham ◽  
R. Ardaillou
Keyword(s):  
Angiotensin Ii ◽  
Mesangial Cells ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Glomerular Mesangial Cells ◽  
Angiotensin Ii Receptor ◽  
Functional Responses ◽  
At1 Antagonists ◽  
Angiotensin Ii Receptor Subtypes ◽  
High Concentrations

This study was designed to identify the subtypes of angiotensin II (ANG II) receptors present on glomeruli and glomerular mesangial cells and establish their functional significance. Dup 753 and its metabolite EXP 3174, two nonpeptide ANG II-1 receptor (AT1) antagonists, displaced 125I-ANG II and its analogue 125I-[Sar1,Ala8]ANG II from their binding sites in rat and human glomeruli and cultured human mesangial cells, whereas CGP 42112 A and PD 123177, two ANG II-2 receptor (AT2) antagonists, exhibited little displacing activity. Dup 753 and EXP 3174 did not modify the dissociation constant (Kd) value but markedly decreased the number of sites of 125I-[Sar1,Ala8]ANG II binding. The addition of PD 123177 did not further inhibit binding when all AT1 sites were occupied by Dup 753. Binding was markedly reduced by dithiothreitol. EXP 3174 and Dup 753 inhibited the main biological functions of ANG II in mesangial cells including increases in intracellular calcium concentration, PGE2 production, and protein synthesis. PD 123177 was also active but at concentrations 1,000- to 10,000-fold greater than those of AT1 antagonists. These results indicate that 1) only AT1 receptors are present in glomeruli and glomerular mesangial cells; 2) these receptors mediate the functional responses to ANG II; 3) the nonpeptide AT1 antagonists behave as noncompetitive inhibitors; and 4) high concentrations of the nonpeptide AT2 antagonists can recognize AT1 sites.

Vasoconstrictor-evoked prostaglandin synthesis in cultured human mesangial cells

1985 ◽  
Vol 248 (2) ◽  
pp. F240-F246 ◽  
Author(s):  
N. Ardaillou ◽  
J. Hagege ◽  
M. P. Nivez ◽  
R. Ardaillou ◽  
D. Schlondorff
Keyword(s):  
Arginine Vasopressin ◽  
Mesangial Cells ◽  
Platelet Activating Factor ◽  
Feedback Mechanism ◽  
Ang Ii ◽  
Glomerular Mesangial Cells ◽  
Human Mesangial Cells ◽  
Cell Contractility ◽  
Human Glomerular Mesangial Cells ◽  
Cells Cultured

We examined the influence of angiotensin II (ANG II), arginine vasopressin (AVP), and platelet activating factor (PAF) on prostaglandin (PG) synthesis and cell contractility in human glomerular mesangial cells in culture. Addition of sodium butyrate to the culture medium for 40 h significantly increased synthesis of both 6-keto-PGF1 alpha and PGE2 in the presence of exogenous arachidonic acid and of PGE2 under basal conditions. To optimize conditions in all further experiments, cells cultured with butyrate were studied. Under basal conditions, cultured mesangial cells produced predominantly 6-keto-PGF1 alpha and much less PGE2. Addition of either ANG II, AVP, or PAF all resulted in a rapid (within minutes) two- to threefold stimulation of 6-keto-PGF1 alpha and PGE2. Threshold stimulations were obtained at 10 pM for ANG II, 1 nM for AVP, and 10-100 pM for PAF. Preincubation of the cells with [Sar1,Ala8]ANG II, an antagonist of ANG II, inhibited ANG II-enhanced PG production, and preincubation with 1-desamino-8-D-arginine vasopressin, an antidiuretic analogue, blunted AVP-enhanced PG production. Under phase-contrast microscopy, PAF, ANG II, and, to a lesser degree, AVP caused decrease in cell surface area of mesangial cells cultured without butyrate at concentrations similar to those stimulating PG synthesis. Only PAF contracted cells cultured with butyrate, indicating attenuation of the vasoactive effects of ANG II and AVP when synthesis of PG was increased. However, a lower dose of PAF was only active when PG synthesis was inhibited, suggesting the same feedback mechanism for the three agonists.

Effects of angiotensin II and vasopressin on intracellular pH of glomerular mesangial cells

1988 ◽  
Vol 254 (6) ◽  
pp. F787-F794 ◽  
Author(s):  
M. B. Ganz ◽  
G. Boyarsky ◽  
W. F. Boron ◽  
R. B. Sterzel
Keyword(s):  
Angiotensin Ii ◽  
Intracellular Ph ◽  
Mesangial Cells ◽  
Ang Ii ◽  
Glomerular Mesangial Cells ◽  
Initial Value ◽  
Ph Change ◽  
Acid Load ◽  
Ethanesulfonic Acid ◽  
Acid Extrusion

We investigated changes in intracellular pH (pHi) of cultured rat glomerular mesangial cells (MCs) exposed to angiotensin II (ANG II) and arginine vasopressin (AVP). pHi of quiescent MCs, passage 2–5, and grown on glass cover slips, was assessed by spectrofluorometry using the pH-sensitive dye, 2,7-biscarboxyethyl-5(6)-carboxyfluorescein (BCECF). The steady-state pHi of MCs in a pH 7.4, HCO3-free N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES)-buffered solution was 7.10 +/- 0.02 (n = 68) and in a pH 7.4, HCO3-containing solution, was 7.23 +/- 0.03 (n = 47) (P less than 0.01). The pHi recovery following an NH+4-induced acid load was inhibited by removal of Na+ from the bath or by addition of the amiloride analogue, ethyl isopropyl amiloride (EIPA). These effects were observed in MCs bathed in HEPES- or in HCO3-buffered solutions, consistent with the action of a Na+-H+ exchanger. When cells were bathed in HEPES, a 10-min exposure to ANG II or AVP (10(-10) to 10(-6) M) caused early and transient acidification of MCs (maximal pH change was -0.10), followed by gradual alkalinization (maximal pHi change +0.15 above the initial value). The increase of pHi was dependent on the presence of Na+ in the bath and was inhibited by EIPA. In the presence of HCO3, ANG II or AVP induced merely a small gradual acidification of MCs (pHi change -0.05). These findings demonstrate that MCs utilize a Na+-H+ exchanger for acid extrusion.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Angiotensin II-induced ERK1/ERK2 activation and protein synthesis are redox-dependent in glomerular mesangial cells

2004 ◽  
Vol 381 (1) ◽  
pp. 231-239 ◽  
Author(s):  
Yves GORIN ◽  
Jill M. RICONO ◽  
Brent WAGNER ◽  
Nam-Ho KIM ◽  
Basant BHANDARI ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Protein Synthesis ◽  
Angiotensin Ii ◽  
Mesangial Cells ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Ang Ii ◽  
Glomerular Mesangial Cells ◽  
Diphenylene Iodonium ◽  
Erk2 Activation

Angiotensin II (Ang II) stimulates hypertrophy of glomerular mesangial cells. The signalling mechanism by which Ang II exerts this effect is not precisely known. Downstream potential targets of Ang II are the extracellular-signal-regulated kinases 1 and 2 (ERK1/ERK2). We demonstrate that Ang II activates ERK1/ERK2 via the AT1 receptor. Arachidonic acid (AA) mimics the action of Ang II on ERK1/ERK2 and phospholipase A2 inhibitors blocked Ang II-induced ERK1/ERK2 activation. The antioxidant N-acetylcysteine as well as the NAD(P)H oxidase inhibitors diphenylene iodonium and phenylarsine oxide abolished both Ang II- and AA-induced ERK1/ERK2 activation. Moreover, dominant-negative Rac1 (N17Rac1) blocks activation of ERK1/ERK2 in response to Ang II and AA, whereas constitutively active Rac1 resulted in an increase in ERK1/ERK2 activity. Antisense oligonucleotides for Nox4 NAD(P)H oxidase significantly reduce activation of ERK1/ERK2 by Ang II and AA. We also show that protein synthesis in response to Ang II and AA is inhibited by N17Rac1 or MEK (mitogen-activated protein kinase/ERK kinase) inhibitor. These results demonstrate that Ang II stimulates ERK1/ERK2 by AA and Nox4-derived reactive oxygen species, suggesting that these molecules act as downstream signal transducers of Ang II in the signalling pathway linking the Ang II receptor AT1 to ERK1/ERK2 activation. This pathway involving AA, Rac1, Nox4, reactive oxygen species and ERK1/ERK2 may play an important role in Ang II-induced mesangial cell hypertrophy.

Effect of angiotensin II on Ca2+ kinetics and contraction in cultured rat glomerular mesangial cells

1988 ◽  
Vol 254 (2) ◽  
pp. F254-F266 ◽  
Author(s):  
K. Takeda ◽  
H. Meyer-Lehnert ◽  
J. K. Kim ◽  
R. W. Schrier
Keyword(s):  
Angiotensin Ii ◽  
Cell Shape ◽  
Mesangial Cells ◽  
In Vitro Study ◽  
Ang Ii ◽  
Glomerular Mesangial Cells ◽  
Glomerular Mesangial Cell ◽  
High Potassium ◽  
Voltage Dependent

This in vitro study was undertaken to determine the changes in Ca2+ kinetics and cell shape of cultured putative glomerular mesangial cells in the rat in response to angiotensin II (ANG II). Intracellular Ca2+ ([Ca2+]i) was measured using quin 2. ANG II-stimulated Ca2+ efflux was also determined. ANG II induced rapid concentration-dependent increases in [Ca2+]i and Ca2+ efflux. ANG II also induced contraction of mesangial cells as assessed by alterations in cell shape. Even in Ca2+-free medium, ANG II increased [Ca2+]i and Ca2+ efflux, but to a lesser extent. Under this condition, contraction of mesangial cells induced by ANG II was also observed. Readdition of extracellular Ca2+ after the ANG II-induced increase in [Ca2+]i caused a second and slower [Ca2+]i increase. High potassium (50 mM) induced a change of [Ca2+]i, but to a lesser extent compared with the ANG II-induced change. The Ca2+ channel blocker verapamil (5 x 10(-5) M) partially inhibited ANG II-induced Ca2+ influx but totally blocked the increase in [Ca2+]i induced by high potassium. Verapamil did not inhibit ANG II-stimulated Ca2+ efflux or the change in cell shape. Dantrolene (10(-4) M), a blocker of Ca2+ release from endoplasmic reticulum, inhibited ANG II-stimulated Ca2+ efflux and change in cell shape. These results indicate that ANG II rapidly increases [Ca2+]i in cultured rat mesangial cells, in part by mobilizing Ca2+ from dantrolene-sensitive intracellular pools and in part through activation of receptor-operated and voltage-dependent Ca2+ channels. The [Ca2+]i mobilization, however, seems to be the primary modulator of initial glomerular mesangial cell contraction.

Extracellular glucose reduces the responsiveness of mesangial cell ion channels to angiotensin II

1995 ◽  
Vol 269 (3) ◽  
pp. F389-F397 ◽  
Author(s):  
E. E. Seal ◽  
D. C. Eaton ◽  
L. M. Gomez ◽  
H. Ma ◽  
B. N. Ling
Keyword(s):  
Angiotensin Ii ◽  
Ion Channels ◽  
High Glucose ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Ion Homeostasis ◽  
Ang Ii ◽  
Glomerular Mesangial Cells ◽  
Extracellular Glucose ◽  
Normal Glucose

Abnormal cellular ion homeostasis is a well-recognized component of diabetic glomerular disease. In cultured rat glomerular mesangial cells, we have previously shown that insulin regulates Ca(2+)-dependent activation of 4-pS Cl- channels and 27-pS nonselective cation channels (NSCC) by angiotensin II (ANG II). To assess whether extracellular glucose also affects mesangial ion channels, we applied patch-clamp techniques to cells incubated in constant insulin (100 mU/ml) and either "normal" (5 mM) or "high" (30 mM) glucose for 1 wk. In normal glucose, 100 nM ANG II increased Cl- and NSCC activity by > 16-fold and > 60-fold, respectivley. Direct release of intracellular Ca2+ ([Ca2+]i) stores (0.25 microM thapsigargin) mimicked ANG II-induced channel stimulation. In high glucose, Cl- and NSCC stimulation by ANG II was attenuated (< 7-fold), whereas channel activation by thapsigargin was unaffected. Protein kinase C (PKC) inhibition (30-min exposure to 0.5 microM calphostin) or downregulation (24-h exposure to 0.1 microM 4 beta-phorbol 12-myristate 13-acetate), but not aldose reductase inhibition (0.5 mM sorbinil), restored channel responsiveness to ANG II despite high glucose. Channel responsiveness was also restored if mesangial cells were coincubated in both high glucose and 500 microM myo-inositol. Acute exposure to a synthetic diacylglycerol (100 microM 1-oleoyl-2-acetyl glycerol) reestablished channel unresponsiveness to ANG II. We conclude the following in rat mesangial cell cultures: 1) Activation of Ca(2+)-dependent Cl- and NSCCs by ANG II is reduced by high extracellular glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of STAT3/mTOR-regulated autophagy in angiotensin II-induced senescence of human glomerular mesangial cells

2019 ◽  
Vol 53 ◽  
pp. 327-338 ◽  
Author(s):  
Shuang Yang ◽  
Dan Sun ◽  
Lining Wang ◽  
Xiuying Wang ◽  
Mai Shi ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Mesangial Cells ◽  
Glomerular Mesangial Cells ◽  
Human Glomerular Mesangial Cells

Probucol inhibits JAK2−STAT pathway activation and protects human glomerular mesangial cells from tert-butyl hydroperoxide induced premature senescence

2013 ◽  
Vol 91 (9) ◽  
pp. 671-679 ◽  
Author(s):  
Hongli Zhou ◽  
Bo Huang ◽  
Yarong Han ◽  
Ruixia Jin ◽  
Shuo Chen
Keyword(s):  
Protein Expression ◽  
Mesangial Cells ◽  
Morphological Changes ◽  
Glomerular Mesangial Cells ◽  
Butyl Hydroperoxide ◽  
Tert Butyl ◽  
Bax Protein ◽  
Age Related ◽  
Tert Butyl Hydroperoxide ◽  
Stat Pathway

Human mesangial cells (HMCs) have a finite lifespan and eventually enter irreversible growth arrest known as cellular senescence, which is thought to contribute to kidney ageing and age-related kidney disorders such as chronic kidney disease. The JAK2−STAT pathway plays a pivotal role in transmitting cytokine signals, including cell proliferation, apoptosis, and differentiation, but whether it could regulate HMC senescence still remains to be explored. In our study, tert-butyl hydroperoxide (tBHP)-induced cells accelerated HMC senescence, as judged by increased senescence-associated β-galactosidase stained positive cells, morphological changes, and G0−G1 cell cycle arrest. STAT1 and STAT3 activity were increased in tBHP-induced cells. After tBHP treatment, Bcl-2 protein expression decreased and Bax protein expression increased. Blocking the JAK2−STAT pathway with AG490 and using probucol significantly inhibited the progression of HMC senescence. Bax protein expression decreased, but Bcl-2 protein expression increased after AG490 and probucol treatment. Our results indicated that the JAK2−STAT pathway might mediate tBHP-induced HMC senescence through the Bcl-2−Bax pathway, and that probucol could attenuate HMC senescence by regulating STATs.

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