Spironolactone Ameliorates Angiotensin Ii-Induced Renal Damage Via the Inhibition of Ap-1 and Nf-κB

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 723-723
Author(s):  
Joon-Keun Park ◽  
Kolja Stille ◽  
Dominik N Muller ◽  
Erdenechimeg Shagdarsuren ◽  
Ralf Dechend ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Renal Damage ◽  
Interstitial Fibrosis ◽  
Binding Activity ◽  
Ang Ii ◽  
High Systolic Blood Pressure ◽  
Dna Binding Activity ◽  
Human Renin ◽  
Shift Analysis

P168 Recently, clinical trials have demonstrated the efficacy of spironolactone (SPIRO) in men. Nevertheless the molecular mechanism of action not completely understood. Locally generated angiotensin II (ANG II) stimulates aldosterone. Therefore, we have tested the hypothesis that SPIRO ameliorates ANG II-induced renal damage. Furthermore, we investigated the effect of SPIRO on the transcription factors AP-1 and NF-κB. We treated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) from week 5 to 7 with SPIRO (20 mg/kg/d). Plasma aldosterone was significantly increased in dTGR vs. SPIRO treated and non-transgenic (SD) rats (p<0.05). Untreated dTGR showed high systolic blood pressure (182±8 mm Hg), severe renal damage with 150-fold increased albuminuria, vasculopathy and perivascular and interstitial fibrosis. Chronic SPIRO treatment reduced mortality and vasculopathy completely, despite blood pressure levels of 161±11. 24-hour albuminuria was reduced from 59±15 in dTGR to 3.5±2 mg/d; p<0.01). Electrophoretic mobility gel shift analysis demonstrated a reduction of renal AP-1 and NF-κB DNA binding activity after SPIRO treatment. Immunohistological analysis showed that SPIRO also prevented the expression of AP-1 and/or NF-kB regulated matrix molecules fibronectin and laminin. The reno-protective effect of SPIRO was accompanied with a reduction of monocyte/macrophage infiltration. These findings show that blockade of aldosterone signaling ameliorates ANG II-induced renal damage. SPIRO action was at least partially mediated via AP-1 and NF-κB.

Prolonged infusion of angiotensin II into normal rats induces stellate cell activation and proinflammatory events in liver

2003 ◽  
Vol 285 (3) ◽  
pp. G642-G651 ◽  
Author(s):  
Ramón Bataller ◽  
Erwin Gäbele ◽  
Robert Schoonhoven ◽  
Terry Morris ◽  
Mark Lehnert ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Liver Injury ◽  
Cell Activation ◽  
Stellate Cell ◽  
Elevated Serum ◽  
Inflammatory Cells ◽  
Binding Activity ◽  
Ang Ii ◽  
Dna Binding Activity ◽  
Liver Fibrogenesis

Recent evidence indicates that angiotensin II (ANG II) plays an important role in liver fibrogenesis. However, the underlying mechanisms are largely unknown. In advanced chronic liver diseases, circulating levels of ANG II are frequently elevated. We investigated the hepatic effects of prolonged systemic infusion of ANG II in normal rats. Saline or ANG II at subpressor and pressor doses (15 and 50 ng·kg-1·min-1, respectively) were infused to normal rats for 4 wk through a subcutaneous osmotic pump. Infusion of ANG II resulted in liver injury, as assessed by elevated serum liver enzymes. Livers from ANG II-perfused rats showed activation of JNK and ERK as well as increased NF-κB and activating protein-1 DNA-binding activity. Moreover, ANG II perfusion induced oxidative stress, increased concentration of proinflammatory cytokines, and upregulated the inflammatory proteins inducible nitric oxide synthase and cyclooxygenase-2. Histological examination of the livers from ANG II-infused rats showed mild portal inflammation as well as thickening and thrombosis of small hepatic vessels. ANG II-treated livers showed accumulation of CD43-positive inflammatory cells and activated hepatic stellate cells (HSCs) at the pericentral areas. A slight increase in collagen synthesis was observed, as assessed by Sirius red staining and hepatic hydroxyproline. All of these effects were observed when ANG II was perfused at subpressor and pressor doses. ANG II also accelerated the activation of primary cultured rat HSCs. In conclusion, increased systemic ANG II can induce liver injury by promoting proinflammatory events and vascular damage. ANG II-induced hepatic effects are not dependent on increase in arterial pressure.

Renal Anti-Fibrotic Effect of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension

2020 ◽  
Vol 51 (2) ◽  
pp. 119-129 ◽  
Author(s):  
Giovanna Castoldi ◽  
Raffaella Carletti ◽  
Silvia Ippolito ◽  
Massimiliano Colzani ◽  
Francesca Barzaghi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Diabetic Patients ◽  
Type I ◽  
Ang Ii ◽  
Collagen Expression ◽  
Sodium Glucose Cotransporter ◽  
Inflammatory Infiltrates

Background: Clinical trials have shown that empagliflozin (Empa), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, promotes nephroprotective effects in diabetic patients. The mechanisms underlying nephroprotection are not completely known and it is not known whether the renal beneficial action is present even in non-diabetic kidney disease. The aim of this study was to evaluate the effect of Empa administration on the development of renal fibrosis in an experimental model of angiotensin II (Ang II)-dependent hypertension. Methods: Sprague Dawley rats (n = 31) were divided into 4 experimental groups. Ang II (200 ng/kg/min, osmotic minipumps, s.c., n = 9) or Ang II + Empa (10 mg/kg/day, per os, n = 10) were administered for 2 weeks. Control rats were treated with placebo (physiological saline, n = 6), and another group was treated with placebo plus Empa (n = 6) for the same period. Blood pressure (plethysmographic method) was measured at the beginning and at the end of the experimental protocol. After 2 weeks, the rats were euthanized and the kidneys were excised for histomorphometric evaluation of glomerular and tubulo-interstitial fibrosis and for the immunohistochemical evaluation of inflammatory infiltrates (monocytes/macrophages) and types I and IV collagen expression. Results: The administration of Ang II resulted in an increase in blood pressure (p < 0.01), glomerular (p < 0.05) and tubulo-interstitial (p < 0.01) fibrosis, renal inflammatory infiltrates (p < 0.01) and type I (p < 0.01) and type IV collagen expression (p < 0.05) compared to the control group. Treatment with Empa did not significantly modify the increase in blood pressure due to Ang II, but prevented the development of renal glomerular and tubulo-interstitial fibrosis, and the increase in inflammatory infiltrates and types I and IV collagen expression in Ang II-treated rats (p < 0.01). Conclusions: These data demonstrate that the treatment with Empa prevents the development of renal fibrosis in Ang II-dependent hypertension. In Ang II-dependent hypertension, the anti-fibrotic effect due to SGLT2 inhibition is caused by the reduction of inflammatory infiltrates and it is independent on the modulation of blood pressure increase.

scholarly journals Renal injury in angiotensin II+l-NAME-induced hypertensive rats is independent of elevated blood pressure

2011 ◽  
Vol 300 (4) ◽  
pp. F1008-F1016 ◽  
Author(s):  
Aaron J. Polichnowski ◽  
Limin Lu ◽  
Allen W. Cowley
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Renal Injury ◽  
Interstitial Fibrosis ◽  
Left Kidney ◽  
Fold Increase ◽  
Experimental Hypertension ◽  
Human Populations ◽  
Ang Ii ◽  
Sprague Dawley

The balance between angiotensin II (ANG II) and nitric oxide plays an important role in renal function and is thought to contribute to the progression of renal injury in experimental hypertension. In the present study, we investigated the extent of blood pressure (BP)-dependent and BP-independent pathways of renal injury following 2 wk of hypertension produced by intravenous infusion of ANG II (5 ng·kg−1·min−1)+ Nω-nitro-l-arginine methyl ester (l-NAME; 1.4 μg·kg−1·min−1) in male Sprague-Dawley rats. An aortic balloon occluder was positioned between the renal arteries to maintain (24 h/day) BP to the left kidney (servo-controlled) at baseline levels, whereas the right kidney (uncontrolled) was chronically exposed to elevated BP. Over the 14-day experimental protocol, the average BP to uncontrolled kidneys (152.7 ± 1.8 mmHg) was significantly elevated compared with servo-controlled (113.0 ± 0.2 mmHg) kidneys and kidneys from sham rats (108.3 ± 0.1 mmHg). ANG II+l-NAME infusion led to renal injury that was focal in nature and mainly confined to the outer medulla. Despite the differences in BP between servo-controlled and uncontrolled kidneys, there was a similar ∼3.5-fold increase in renal outer medullary tubular injury, ∼2-fold increase in outer medullary interstitial fibrosis, ∼2-fold increase in outer medullary macrophage infiltration, and a significant increase in renal oxidative stress, all of which are indicative of BP-independent mediated pathways. The results of this study have important implications regarding the pathogenesis of renal injury in various experimental models of hypertension and provide novel insights regarding the variable association observed between hypertension and renal injury in some human populations.

Angiotensin II Promotes Anti-Apoptosis Via Akt-Kinase Phosphorylation, an Effect Ameliorated by High Dose Aspirin

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 679-680
Author(s):  
Dominik N Muller ◽  
Erdenechimeg Shagdarsuren ◽  
Franziska Hampich ◽  
Ralf Dechend ◽  
Joon-Keun Park ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Binding Activity ◽  
High Dose ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Akt Kinase ◽  
Akt Phosphorylation ◽  
Dna Binding Activity ◽  
Dose Aspirin ◽  
High Dose Aspirin

11 The balance between cell proliferation and apoptosis is essential for physiological function. We tested the hypothesis that angiotensin II (ANG II) has anti-apoptotic effects via the activation of AKT kinase in rats overexpressing the human renin and angiotensinogen genes (dTGR). dTGR are hypertensive (182±8 mm Hg) with severe renal damage (150-fold increased albuminuria), perivascular and interstitial fibrosis and vasculopathy, and die at 7 weeks. Renal NF-κB DNA binding activity is increased. We studied the time course of the pathogenesis from week 5 to week 7. Blood pressure, albuminuria, fibrosis, vasculopathy and monocyte infiltration increased over time. In contrast, KI-67 proliferating cells were more abundant in week 5 compared to week 7 as well as compared to non-transgenic rats. Phosphorylation of AKT kinase increased with the severity of the disease. Immunostaining of p-AKT and the activated NF-κB subunit p65 were observed in the glomeruli and endothelium. While Bcl-2 and phosphorylated Bad was predominantly expressed in the endothelium in week 7, the strongest bax immunostaining in the vessel wall media was observed in week 5. We then investigated the effect of chronic high dose aspirin (ASA; 600 mg/kg/d) on remodeling. While ASA did not change blood pressure, albuminuria and fibrosis were similar to non-transgenic controls. ASA completely normalized AKT protein synthesis as well as AKT phosphorylation and NF-κB DNA binding activity. Bax immunostaining at week 7 increased in the media, while Bcl-2 decreased. Western blot in dTGR kidney homogenates showed increased Bcl-2 levels compared ASA-treated and non-transgenic rats. We then confirmed the effect of ASA on p-AKT stimulating endothelial cells in vitro with ANG II (10-7 M; 10 min). Western blot showed reduced p-AKT in ASA pretreated cells. These results show that ANG II is anti-apoptotic by activating AKT kinase. ASA is able to restore the impaired balance of tissue remodeling. Finally, in addition to inhibiting I-κB kinase, ASA may exert a part of its ameliorating effects in this model by inhibiting AKT phosphorylation.

Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1–7)

2007 ◽  
Vol 292 (2) ◽  
pp. H736-H742 ◽  
Author(s):  
Justin L. Grobe ◽  
Adam P. Mecca ◽  
Melissa Lingis ◽  
Vinayak Shenoy ◽  
Tonya A. Bolton ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Cardiac Tissue ◽  
Interstitial Fibrosis ◽  
Chronic Hypertension ◽  
Ang Ii ◽  
Myocyte Hypertrophy ◽  
Chronic Infusion

Cardiac remodeling, which typically results from chronic hypertension or following an acute myocardial infarction, is a major risk factor for the development of heart failure and, ultimately, death. The renin-angiotensin system (RAS) has previously been established to play an important role in the progression of cardiac remodeling, and inhibition of a hyperactive RAS provides protection from cardiac remodeling and subsequent heart failure. Our previous studies have demonstrated that overexpression of angiotensin-converting enzyme 2 (ACE2) prevents cardiac remodeling and hypertrophy during chronic infusion of angiotensin II (ANG II). This, coupled with the knowledge that ACE2 is a key enzyme in the formation of ANG-(1–7), led us to hypothesize that chronic infusion of ANG-(1–7) would prevent cardiac remodeling induced by chronic infusion of ANG II. Infusion of ANG II into adult Sprague-Dawley rats resulted in significantly increased blood pressure, myocyte hypertrophy, and midmyocardial interstitial fibrosis. Coinfusion of ANG-(1–7) resulted in significant attenuations of myocyte hypertrophy and interstitial fibrosis, without significant effects on blood pressure. In a subgroup of animals also administered [d-Ala7]-ANG-(1–7) (A779), an antagonist to the reported receptor for ANG-(1–7), there was a tendency to attenuate the antiremodeling effects of ANG-(1–7). Chronic infusion of ANG II, with or without coinfusion of ANG-(1–7), had no effect on ANG II type 1 or type 2 receptor binding in cardiac tissue. Together, these findings indicate an antiremodeling role for ANG-(1–7) in cardiac tissue, which is not mediated through modulation of blood pressure or altered cardiac angiotensin receptor populations and may be at least partially mediated through an ANG-(1–7) receptor.

Dexamethasone Inhibits Nf-κB, P22phox, and Protects Against Angiotensin Ii-Induced Renal Damage

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 723-723
Author(s):  
Dominik N Muller ◽  
Ralf Dechend ◽  
Franziska Hampich ◽  
Joon-Keun Park ◽  
Anette Fiebeler ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Dna Binding ◽  
Blood Pressure Reduction ◽  
Organ Damage ◽  
Binding Activity ◽  
Mobility Shift ◽  
Cardiac Damage ◽  
End Organ Damage ◽  
Dna Binding Activity

P167 We recently reported that NF-κB activation promotes inflammation in rats harboring both human renin and angiotensinogen genes (dTGR). We now tested the hypothesis that dexamethasone (DEX) inhibits NF-κB and ameliorates renal and cardiac end-organ damage. The dTGR feature moderate hypertension, severe renal, and cardiac damage, as well as over 50% mortality at 7 weeks. Immunohistochemical analysis shows increased infiltration of monocytes and T-cells. Electrophoretic mobility shift assay showed increased NF-κB DNA binding activity in heart and kidney of dTGR. One-week treatment with DEX (1 mg/kg/d i.p.) initially increased blood pressure at week 5, compared to dTGR (191±2 vs.152±6 mm Hg, p<0.01), whereas blood pressure was not different at week 7 (193±15 vs. 182±8 mm Hg, p=0.8). However, DEX reduced 24 h albuminuria by 85 % (2.7±0.5 vs. 18.0±3.4 mg/d, p<0.001) and prevented mortality completely. Vasculopathy was ameliorated in kidney and heart and perivascular fibrosis was reduced. DEX inhibited NF-κB DNA-binding activity and also the NF-κB-regulated adhesion molecule ICAM-1. We also studied localization of NADPH subunit p22phox. Immunostaining of p22phox was detected in the endothelium and also colocalized with monocytes. DEX reduced both infiltration of cells and p22phox expression. Thus, these results demonstrate that DEX suppresses NF-κB binding activity, p22phox expression of infiltrated cells, inflammation, and protects against angiotensin II-induced end-organ damage, all without blood pressure reduction.

scholarly journals Activation of glomerular mitogen-activated protein kinases in angiotensin II-mediated hypertension.

1998 ◽  
Vol 9 (3) ◽  
pp. 372-380 ◽  
Author(s):  
A Hamaguchi ◽  
S Kim ◽  
M Yano ◽  
S Yamanaka ◽  
H Iwao
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinases ◽  
Binding Activity ◽  
Ang Ii ◽  
Glomerular Injury ◽  
Mitogen Activated Protein Kinases ◽  
Dna Binding Activity ◽  
Induced Hypertension ◽  
Mitogen Activated Protein

The in vivo signal transduction pathway, responsible for hypertension-induced glomerular injury, remains to be clarified. In this study, the effect of angiotensin II (Ang II)-induced hypertension was examined on glomerular mitogen activated protein kinases (MAPK), including extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK), and on glomerular transcription factors activator protein-1 (AP-1) and Sp 1. MAPK activities were determined by in-gel kinase assay. DNA binding activity of AP-1 and Sp 1 was determined by gel mobility shift assay. Continuous infusion of Ang II (1000 ng/kg per min, intravenously) to conscious rats rapidly increased BP, followed by the rapid and transient activation of glomerular p42 and p44 ERK and p46 and p55 JNK with the peak at 15 to 180 min. Glomerular AP-1 binding activity was increased 2.6-fold (P < 0.01) at 24 h after the start of Ang II infusion. Supershift analysis showed that the activated AP-1 complexes contained c-Fos and c-Jun proteins. On the other hand, glomerular Sp 1 DNA binding activity was not changed throughout 7 d of Ang II infusion. These results provided the first in vivo evidence that Ang II-induced hypertension causes the activation of glomerular ERK and JNK, leading to the activation of AP-1. Thus, ERK and JNK signaling cascades, via the activation of AP-1, may be implicated in the development of hypertension-induced glomerular injury.

scholarly journals Blocking of interleukin-1 suppresses both angiotensin II-induced renal inflammation and hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Niida ◽  
K Isoda ◽  
K Kitamura ◽  
Y Okabayashi ◽  
T Kadoguchi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Angiotensin Ii ◽  
Renal Damage ◽  
Interleukin 1 ◽  
Funding Source ◽  
Ang Ii ◽  
Glomerular Injury ◽  
Renal Inflammation ◽  
Induced Hypertension

Abstract Background Clinical hypertension is associated with renal inflammation and elevated circulating levels of proinflammatory cytokines. IL-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines and plays a crucial role in inflammation. Inhibition of IL-1 may contribute to modulation of the Angiotensin II (AngII)-induced hypertension response. This study aimed to elucidate the effects of IL-1Ra and anti-IL-1beta antibody (01BSUR) on AngII-induced hypertension and renal inflammation. Methods and results To determine the contribution of IL-1Ra to AngII-induced renal inflammation, male wild-type (WT) and IL-1Ra-deficient (IL-1Ra−/−) mice were infused with AngII (1000ng/kg/min) using subcutaneous osmotic pumps for 14 days. We checked blood pressure, histological change, and several mRNA expressions 14 days after infusion. Fourteen days after infusion, systolic blood pressure (197±5 vs 169±9 mmHg, p&lt;0.05) in IL-1Ra−/− mice significantly increased compared with WT mice. Furthermore, on day 14 of AngII infusion, plasma IL-6 was 5.9-fold higher in IL-1Ra−/− versus WT mice (p&lt;0.001); renal preproendothelin-1 mRNA expression was also significantly higher in IL-1Ra−/− mice (p&lt;0.05). To examine renal function, we analyzed 24-hour urinary protein excretion and serum levels of blood urea nitrogen, creatinine, and uric acid in IL-1Ra−/− and WT mice. On day 14 of Ang II infusion, all levels increased significantly in IL-1Ra−/− mice compared with WT mice, suggesting that IL-1Ra deficiency reduced renal function following Ang II infusion. In addition, renal histology revealed that glomerular injury (Figure upper panels: PAS staining) and tubulointerstitial fibrosis (Figure lower panels: Elastica Masson staining) increased significantly in Ang II-infused IL-1Ra−/− versus Ang II-infused WT mice. Finally, we administrated 01BSUR to both IL-1Ra−/− and WT mice, and 01BSUR treatment decreased AngII-induced hypertension (162±17 vs 204±6 mmHg, p&lt;0.05) and renal damage (glomerular injury and fibrosis of the tubulointerstitial area) in both IL-1Ra−/− and WT mice compared with IgG2a treatment. These findings suggest that 01BSUR suppresses Ang II-induced inflammation and renal injury. Conclusions Inhibition of interleukin-1 by both endogenous IL-1Ra and exogenous 01BSUR decreased AngII-induced hypertension and renal damage in mice, suggesting suppression of IL-1 may provide an additional strategy to protect against renal damage in hypertensive patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): JSPS KAKENHI

scholarly journals Endoplasmic reticulum and oxidant stress mediate nuclear factor-κB activation in the subfornical organ during angiotensin II hypertension

2015 ◽  
Vol 308 (10) ◽  
pp. C803-C812 ◽  
Author(s):  
Colin N. Young ◽  
Anfei Li ◽  
Frederick N. Dong ◽  
Julie A. Horwath ◽  
Catharine G. Clark ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Bioluminescence Imaging ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Ang Ii ◽  
Arterial Blood

Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.

Sign in / Sign up

Export Citation Format

Share Document