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.

Abstract P363: Annexin-A1 Deficiency Exaggerates Cardiac Remodeling In Angiotensin II-induced Hypertension

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Kristy Jackson ◽  
Jaideep Singh ◽  
Yen Zhi Ng ◽  
Cheng Peng ◽  
Anida Velagic ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Physiological Role ◽  
Preclinical Model ◽  
Annexin A1 ◽  
Ang Ii ◽  
Cardiac Damage ◽  
Induced Hypertension ◽  
Deficient Mice

Introduction: We have previously demonstrated that the naturally-occurring anti-inflammatory and pro-resolving protein Annexin-A1 (Anx-A1) limits the acute inflammatory response post myocardial infarction, but its impact on chronic inflammation, such as hypertension, has not been explored. This study aims to investigate the role of Anx-A1 in a preclinical model of hypertension, induced by angiotensin-II (Ang-II). Methods: 15-week-old male C57BL/6 or ANXA1 -/- were anesthetized (isoflurane, 2-4% v/v) and implanted with an osmotic minipump randomly assigned to receive Ang-II (0.7mg/kg/day) or vehicle (saline). Radiotelemetry recordings of blood pressure were taken at 10 intermittent timepoints from baseline to the end of the 29-day infusion period. Animals were euthanized with pentobarbitone (100mg/kg; i.p.) at endpoint and organ weights recorded and normalized to bodyweight. Left ventricle (LV) samples were stained with picrosirius red to assess total LV collagen deposition. Results: Ang II-induced mice at the end of the study had elevated mean arterial pressure (MAP), cardiac hypertrophy and fibrosis compared to normotensive mice (Table). Anx-A1 deficient mice given Ang II had an even greater increase in MAP and cardiac remodeling compared to WT. Interestingly, MAP of Anx-A1 deficient mice at baseline is significantly higher compare to C57BL/6 counterparts (Table). Conclusion: This is the first study to demonstrate that deficiency of Anx-A1 exaggerates cardiac remodeling in AngII-induced hypertension, suggesting that endogenous Anx-A1 might play previously unappreciated physiological role in regulating blood pressure. This supports the development of Anx-A1 based pharmacotherapy against hypertension-induced cardiac damage.

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 Dapagliflozin: a Sodium-glucose Cotransporter 2 Inhibitor, Attenuates Angiotensin II-induced Cardiac Fibrotic Remodeling by Regulating TGFβ1/ Smad Signaling

2021 ◽  
Author(s):  
Yuze Zhang ◽  
Xiaoyan Lin ◽  
Yong Chu ◽  
Xiaoming Chen ◽  
Heng Du ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Sglt2 Inhibitor ◽  
Left Ventricular ◽  
Ang Ii ◽  
Smad Signaling ◽  
Sd Rats ◽  
Sodium Glucose Cotransporter ◽  
Tgf Β1

Abstract Background:Cardiac remodeling is one of the major risk factors for heart failure. In patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of the first hospitalization for heart failure, possibly through glucose-independent mechanisms, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing cardiac remodeling and potential mechanisms.Methods:Sprague-Dawley (SD) rats, induced by chronic infusion of Angiotensin II (Ang II) at a dose of 520 ng/kg per minute for 4 weeks with ALZET® mini-osmotic pumps, were treated with either SGLT2 inhibitor dapagliflozin (DAPA) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with Ang II with or without the indicated concentration of DAPA. The protein levels of collagen and TGF-β1/Smad signaling were measured along with body weight, and blood biochemical indexes.Results:DAPA treatment resulted in the amelioration of left ventricular dysfunction in Ang II-infused SD rats without affecting blood glucose and blood pressure. Myocardial hypertrophy, fibrosis and increased collagen synthesis caused by Ang II infusion were significantly inhibited by DAPA treatment. In vitro, DAPA inhibit the Ang II-induced collagen production of CFs. Immunoblot with heart tissue homogenates from chronic Ang II-infused rats revealed that DAPA inhibited the activation of TGF-β1/Smads signaling.Conclusion:DAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-β1/Smad signaling in a glucose-independent manner. DAPA may serve as a novel therapy for pathological cardiac remodeling.

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.

scholarly journals 586 Effect of sacubitril/valsartan combination in an experimental model of heart failure

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Antonella De Angelis ◽  
Donato Cappetta ◽  
Marialucia Telesca ◽  
Gabriella Bellocchio ◽  
Konrad Urbanek ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Angiotensin Ii ◽  
Left Ventricle ◽  
Diastolic Function ◽  
Cardiac Tissue ◽  
Function Analysis ◽  
Social Burden ◽  
Systolic And Diastolic Function ◽  
Tail Cuff

Abstract Aims The majority of elderly patients with heart failure has a preserved ejection fraction (HFpEF) that constitutes a syndrome characterized by frequent hospitalizations and high mortality. Despite the growing social burden of HFpEF, the comprehension of its pathophysiology is incomplete, and treatment remains largely undefined. Ageing itself may contribute independently to deterioration of diastolic function. Methods and results An 18-month-old female Fischer 344 rats were treated with oral administration of either sacubitril/valsartan (60 mg/kg/die, 1:1 ratio) or valsartan alone (30 mg/kg/die) for 12 weeks. Tail-cuff method was used to monitor blood pressure weekly. Echocardiography and left ventricle catheterization were employed to assess systolic and diastolic function, at baseline, and before sacrifice. Cardiac tissue was used for molecular biology and histochemistry assays. Tail-cuff analysis indicated a comparable decrease in blood pressure between treatments. Hypertrophy also showed a significant reduction with both treatments. On the contrary, myocardial function analysis demonstrated that no treatment was efficacy on diastolic dysfunction. The lack of improvement of cardiac function could be attributed to the inability of the treatments to counteract the accumulation of fibrotic tissue in the left ventricle, which, in turn, is attributable to the failure to reduce the inflammatory process and oxidative stress, and to the inability to modulate angiotensin II pathway. Conclusions Our results evidenced that both sacubitril/valsartan or valsartan treatment was able to improve diastolic function and pro-fibrotic remodelling, partly due to a lack of effect on classical and non-classical pathways of angiotensin II.

Abstract 300: Oral Administration of Lentil Extracts Attenuated Angiotensin Ii-induced Cardiac Hypertrophy and Hypertension in Normotensive Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Chengluan Xuan ◽  
Fanrong Yao ◽  
Lirong Guo ◽  
Sam Chang ◽  
Kexiang Liu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Oral Administration ◽  
Protective Effect ◽  
Cardiac Tissue ◽  
Direct Action ◽  
Ang Ii ◽  
Subcutaneous Infusion ◽  
Cultured Cardiomyocytes

The objective of this study is to examine the effects of extracts from raw and cooked lentil on angiotensin II (Ang II)-induced cardiac hypertrophy, fibrosis, and hypertension in normotensive rats. Subcutaneous infusion of Ang II (200 ng/kg/min) using osmotic minipump significantly resulted in the elevation of blood pressure measured using telemetry in conscious rats. Histological examination revealed that Ang II infusion for 4 weeks induced significant cardiac hypertrophy, perivascular fibrosis in the heart and kidney. Rats received lentil extracts (oral administration for 4 weeks) significantly attenuated Ang II-induced elevation in blood pressure, cardiac hypertrophy, perivascular fibrosis. To examine whether the protective effect of lentil extracts on cardiac hypertrophy is mediated by attenuation of blood pressure or directly act on the cardiomyocytes, we examined the effect of lentil extracts on Ang II-induced hypertrophy in cultured cardiomyocytes. The result demonstrated that pretreatment of cardiomyocytes with cooked or raw lentil extract significantly attenuated the Ang II-induced increases in the size of cells. In addition, these lentil extracts also attenuated Ang II-induced increases in the ROS levels in cardiomyocytes. In summary, the results demonstrate that extracts from cooked or raw lentil prevent Ang II-induced elevation in blood pressure, perivascular fibrosis, and cardiac hypertrophy. The cardiac protective effect on Ang II-induced cardiac hypertrophy may be mediated by a direct action in cardiac tissue via reduction of oxidative stress.

scholarly journals A mouse model of heart failure with preserved ejection fraction due to chronic infusion of a low subpressor dose of angiotensin II

2015 ◽  
Vol 309 (5) ◽  
pp. H771-H778 ◽  
Author(s):  
Jessica A. Regan ◽  
Adolfo Gabriele Mauro ◽  
Salvatore Carbone ◽  
Carlo Marchetti ◽  
Rabia Gill ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Relaxation Time ◽  
Angiotensin Ii ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Low Dose ◽  
Preserved Ejection Fraction ◽  
Arterial Blood ◽  
Chronic Infusion

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents ∼50% of patients with HF, the mechanisms of disease are poorly understood, and therapies are generally ineffective in reducing HF progression. Animal models of HFpEF not due to pressure or volume overload are lacking, therefore limiting in-depth understanding of the pathophysiological mechanisms and the development of novel therapies. We hypothesize that a continuous infusion of low-dose angiotensin II (ATII) is sufficient to induce left ventricular (LV) diastolic dysfunction and HFpEF, without increasing blood pressure or inducing LV hypertrophy or dilatation. Osmotic pumps were implanted subcutaneously in 8-wk-old male mice assigned to the ATII (0.2 mg·kg−1·day−1) or volume-matched vehicle ( N = 8/group) for 4 wk. We measured systolic and diastolic arterial blood pressures through a tail-cuff transducer, LV dimensions and ejection fraction through echocardiography, and LV relaxation through pulsed-wave Doppler and LV catheterization. Myocardial fibrosis and cardiomyocyte cross-sectional area were measured. ATII infusion had no effects on systemic arterial blood pressure. ATII induced significant impairment in LV diastolic function, as measured by an increase (worsening) in LV isovolumetric relaxation time, myocardial performance index, isovolumetric relaxation time constant, and LV end-diastolic pressure without altering LV dimensions, mass, or ejection fraction. Chronic infusion of low-dose ATII recapitulates the HFpEF phenotype in the mouse, without increasing systemic arterial blood pressure. This mouse model may provide insight into the mechanisms of HFpEF.

scholarly journals Dapagliflozin: a sodium–glucose cotransporter 2 inhibitor, attenuates angiotensin II-induced cardiac fibrotic remodeling by regulating TGFβ1/Smad signaling

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Yuze Zhang ◽  
Xiaoyan Lin ◽  
Yong Chu ◽  
Xiaoming Chen ◽  
Heng Du ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Ang Ii ◽  
Smad Signaling ◽  
Sd Rats ◽  
Sodium Glucose Cotransporter ◽  
Tgf Β1

Abstract Background Cardiac remodeling is one of the major risk factors for heart failure. In patients with type 2 diabetes, sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of the first hospitalization for heart failure, possibly through glucose-independent mechanisms in part, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing cardiac remodeling and potential mechanisms. Methods Sprague–Dawley (SD) rats, induced by chronic infusion of Angiotensin II (Ang II) at a dose of 520 ng/kg per minute for 4 weeks with ALZET® mini-osmotic pumps, were treated with either SGLT2 inhibitor dapagliflozin (DAPA) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with Ang II (1 μM) with or without the indicated concentration (0.5, 1, 10 μM) of DAPA. The protein levels of collagen and TGF-β1/Smad signaling were measured along with body weight, and blood biochemical indexes. Results DAPA pretreatment resulted in the amelioration of left ventricular dysfunction in Ang II-infused SD rats without affecting blood glucose and blood pressure. Myocardial hypertrophy, fibrosis and increased collagen synthesis caused by Ang II infusion were significantly inhibited by DAPA pretreatment. In vitro, DAPA inhibit the Ang II-induced collagen production of CFs. Immunoblot with heart tissue homogenates from chronic Ang II-infused rats revealed that DAPA inhibited the activation of TGF-β1/Smads signaling. Conclusion DAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-β1/Smad signaling in a non-glucose-lowering dependent manner.

Abstract 13407: A Mouse Model of Heart Failure with Preserved Ejection Fraction (HFpEF) due to Chronic Infusion of a Low Subpressor Dose of Angiotensin II

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Stefano Toldo ◽  
Carlo Marchetti ◽  
Aysar Al Husseini ◽  
Salvatore Carbone ◽  
Jessica Regan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Angiotensin Ii ◽  
Mouse Model ◽  
Diastolic Function ◽  
Low Dose ◽  
Left Ventricular ◽  
Vehicle Group ◽  
Chronic Infusion ◽  
Lv Diastolic Function

Introduction: Heart failure with preserved ejection fracture (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents approximately 50% of all patients with HF, the mechanisms of disease are poorly understood, animal models of HFpEF not due pressure overload are lacking, and therapies for HFpEF are generally ineffective. Hypothesis: A continuous infusion of low dose of angiotensin II (ATII) may be sufficient to induce changes in left ventricular (LV) diastolic function without increasing blood pressure nor induce LV hypertrophy. Methods: Osmotic pumps were implanted subcutaneously in 8 week-old CD1 male mice randomly assigned to the ATII (200 ng/kg/day) or vehicle (N=8/group). Transthoracic echocardiography was performed at baseline and 4 weeks to measure LV dimensions, systolic and diastolic function. Aortic systolic and diastolic pressures (AoP), LV peak systolic and end-diastolic pressures (LVPSP, LVEDP) were measured at LV catheterization. Fibrosis was measured using Masson’s trichrome stain. The expression of Interleukin (IL)-18 mRNA levels, a cytokine associated with impaired cardiomyocyte relaxation, was measured at 4 weeks. Results: When compared to the baseline values or vehicle group, ATII infusion had no effects on AoP, LVPSP and HR, and had no effects on LV dimensions or mass, nor on LVEF (all P>0.2). ATII induced a significant impairment in LV diastolic function as measured by an increase (worsening) of the myocardial performance index (MPI), the LV isovolumetric relaxation time (IVRT) and of LVEDP (Figure). Cardiac expression of IL-18 mRNA was significantly increased 7-fold after ATII infusion (P<0.001), suggesting a potential mechanistic role of IL-18. Conclusion: Chronic infusion of low dose ATII recapitulates the HFpEF phenotype in the mouse, without increasing blood pressure. The use of this mouse model may help understanding the mechanisms leading to HFpEF syndrome in patients.

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.

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