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 Sodium-glucose cotransporter 2 inhibition prevents renal fibrosis in cyclosporine nephropathy

2021 ◽  
Author(s):  
Giovanna Castoldi ◽  
Raffaella Carletti ◽  
Silvia Ippolito ◽  
Massimiliano Colzani ◽  
Francesca Barzaghi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Tyrosine Hydroxylase ◽  
Renal Fibrosis ◽  
Type Iv Collagen ◽  
Interstitial Fibrosis ◽  
Experimental Period ◽  
Type I ◽  
Collagen Expression ◽  
Type Iv ◽  
Inflammatory Infiltrates

Abstract Aims Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic drugs, are nephroprotective in case of diabetes, but whether a similar beneficial effect may be detectable also in case of chronic non-diabetic kidney diseases remains still unknown. The aim of this study was to evaluate the effects of empagliflozin, a SGLT-2 inhibitor, on the progression of cyclosporine nephropathy, in the absence of diabetes. Methods Sprague Dawley rats (n = 27) have been fed with low-salt diet starting 10 days before the beginning and finished at the end of the experimental period. Cyclosporine-A (CsA, 15 mg/kg/day, intraperitoneal injection, n = 8) and CsA plus empagliflozin (Empa, 10 mg/kg/day, per os, n = 7) were administered for 4 weeks. The control groups were treated with placebo (Control, n = 7) or empagliflozin (Control + Empa, n = 5). Blood pressure (plethysmographic method) was measured at the beginning and at the end of the experimental period. At the end of the experimental protocol, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates (monocytes/macrophages), type I and type IV collagen expression, and tyrosine hydroxylase expression, used as marker of sympathetic nerve activity. Results CsA-treated rats showed a significant increase (p < 0.01) in blood pressure, which was reduced by administration of empagliflozin (p < 0.05). CsA administration caused an increase in glomerular and tubulo-interstitial fibrosis (p < 0.05), renal inflammatory infiltrates (p < 0.05), type I and type IV collagen expression (p < 0.01), and tyrosine hydroxylase expression (p < 0.01) as compared to the control rats and control + Empa-treated rats. Treatment with empagliflozin in CsA-treated rats reduced glomerular (p < 0.01) and tubulo-interstitial fibrosis (p < 0.05), type I and type IV collagen expression (p < 0.01), inflammatory cell infiltration (p < 0.01) and tyrosine hydroxylase expression (p < 0.05), as compared to rats treated with CsA. Conclusion Empagliflozin administration caused a reduction in blood pressure in CsA-treated rats and showed a protective effect on CsA nephropathy by decreasing renal fibrosis, type I and type IV collagen expression, macrophage infiltration and tyrosine hydroxylase expression. These data suggest that empagliflozin promotes nephroprotection also in non-diabetic kidney disease.

P0984SGLT2 INHIBITION PREVENTS RENAL FIBROSIS IN CYCLOSPORINE NEPHROPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Giovanna Castoldi ◽  
Raffaella Carletti ◽  
Silvia Ippolito ◽  
Massimiliano Colzani ◽  
Francesca Barzaghi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Diabetic Nephropathy ◽  
Tyrosine Hydroxylase ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Control Group ◽  
Diabetic Patients ◽  
Protective Effects ◽  
Type 2 Diabetic Patients ◽  
Inflammatory Infiltrates

Abstract Background and Aims Sodium glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic drugs, showed nephroprotection in type 2 diabetic patients. The mechanisms underlying nephroprotection are not completely known and it is unclear whether the nephroprotective effects are present also in non-diabetic nephropathy. The aim of this study was to evaluate the effects of empagliflozin, a SGLT-2 inhibitor, in cyclosporine nephropathy in the absence of diabetes. Method Ten days before the beginning and then during the entire experimental periods, low-salt diet (Teklad 7034) was administered to Sprague Dawley rats. Cyclosporine-A (CsA, 15 mg/kg/day, intraperitoneal injection; n=6) and CsA plus empagliflozin (Empa, 10 mg/kg /day, per os; n=6) were administered for 4 weeks. Control group was treated with placebo (n=6). Blood pressure was measured by plethysmographic method at the beginning and at the end of the experimental period. At the end of the protocol, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates and tyrosine hydroxylase expression, used as marker of symphatetic nerve activity. Results The rats treated with CsA showed a significant increase (p &lt;0.01) in blood pressure, which was slightly reduced by administration of empagliflozin. CsA administration caused an increase in glomerular and tubulo-interstitial fibrosis (p &lt;0.05), renal inflammatory infiltrates (p &lt;0.05) and tyrosine hydroxylase expression (p &lt;0.01) as compared to the control rats. Treatment with empagliflozin reduced glomerular and tubulo-interstitial fibrosis (p &lt;0.05), inflammatory cell infiltration (p &lt;0.01) and tyrosine hydroxylase expression (p &lt;0.01), as compared to CsA-treated rats. Conclusion Empagliflozin administration showed protective effects on cyclosporine nephropathy, decreasing renal fibrosis, macrophage infiltration and tyrosine hydroxylase expression. These data suggest that the nephroprotective role of empagliflozin could not be restricted only to diabetic nephropathy.

scholarly journals Angiotensin type-2 (AT-2)-receptor activation reduces renal fibrosis in cyclosporine nephropathy: evidence for blood pressure independent effect

2016 ◽  
Vol 36 (6) ◽  
Author(s):  
Giovanna Castoldi ◽  
Cira R.T. di Gioia ◽  
Raffaella Carletti ◽  
Francesca Roma ◽  
Gianpaolo Zerbini ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Intraperitoneal Injection ◽  
Renal Fibrosis ◽  
Urinary Albumin Excretion ◽  
Interstitial Fibrosis ◽  
Urinary Albumin ◽  
Collagen Expression ◽  
Inflammatory Infiltrates ◽  
Angiotensin Type

Compound 21 (C21), selective agonist of angiotensin type-2 (AT-2) receptors, shows anti-inflammatory effects in experimental models of hypertension and nephroprotection in diabetes. The aim of the present study was to evaluate the effects of C21 in cyclosporine nephropathy, which is characterized mainly by tubulo-interstitial fibrosis. Ten days before and during the experimental periods, low-salt diet was administered to Sprague–Dawley rats. Cyclosporine-A (CsA; 15 mg/kg per day, intraperitoneal injection) and CsA plus C21 (0.3 mg/kg per day, intraperitoneal injection) were administered for 1 and 4 weeks. Control groups were left without any treatment. Blood pressure (plethysmographic method) and 24 h urinary albumin excretion were measured once a week. At the end of the experimental protocols, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates and type I and type IV collagen expression. After 1 and 4 weeks, the rats treated with CsA showed a significant increase (P<0.01) in blood pressure, no significant changes in urinary albumin excretion and a significant increase (P<0.01) in glomerular and tubulo-interstitial fibrosis and inflammatory infiltrates as compared with the control rats. Treatment with C21 did not modify the CsA dependent increase of blood pressure, which was higher than in control rats, but after 4 weeks of treatment significantly reduced (P<0.01) glomerular and tubulo-interstitial fibrosis, type 1 collagen expression and macrophage infiltration, as compared with rats treated with cyclosporine. The administration of C21 showed a protective effect on cyclosporine nephropathy, decreasing renal fibrosis and macrophage infiltration. These data suggest that C21 may counteract tubulo-interstitial fibrosis, the most potent predictor of the progression of renal diseases.

Abstract 1494: Hepatocyte Growth Factor Attenuates Angiotensin II Induced Renal Fibrosis through TGF-β1 Suppression by Anoikis of Myofibroblasts

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kazuma Iekushi ◽  
Yoshiaki Taniyama ◽  
Junya Azuma ◽  
Fumihiro Sanada ◽  
Norio Dosaka ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Renal Fibrosis ◽  
Type I ◽  
Ang Ii ◽  
Wild Type ◽  
Induced Apoptosis ◽  
Hepatocyte Growth ◽  
Tgf Β1

Progression of chronic kidney disease (CKD) is characterized by the persistent accumulation of extracellular matrix. Especially, α-SMA positive myofibroblast which produce high amounts of TGF-β1 are considered to play a key role in interstitial fibrosis. Previous studies demonstrated that hepatocyte growth factor (HGF) improved kidney fibrosis in murine models, where direct molecular mechanisms of myofibroblasts have not yet been understood. We tested the hypothesis in vivo using cardiac specific overexpression HGF mice (HGF-Tg), which showed a significant increase in serum HGF concentration. Angiotensin II (Ang II) infusion significantly induced renal fibrosis in wild type mice, while renal fibrosis was significantly decreased in HGF-Tg mice accompanied by the degrease in interstitial myofibroblasts (P<0.05). Quantitative analysis demonstrated 1.69-folds induction of profibrtic cytokine, TGF-β1 mRNA in HGF-Tg with Ang II group compared with wild type with Ang II, and Collagen type I and IV mRNA expression was significantly decreased in HGF-Tg mice with Ang II. The antifibotic action of HGF-Tg mice was concordant with an increase in MMP-2, MMP-9 expression (1.32-fold, 1.33-fold vs wild type with Ang II infusion, P<0.05, respectively), and decreased TIMP-1, TIMP-2 expression (1.5-fold, 1.28-fold vs wild type with Ang II infusion, P<0.05, respectively). To further investigate the anti-fibrotic effect of HGF, we used cultured human mesangial cells (HMC). When HMC were treated with TGF-β1, cells underwent to phenotypic change similar to myofibroblasts, accompanied by the significant increase in c-Met/HGF receptor (P<0.05). Under such conditions, HGF induced anoikis-induced apoptosis of myofibroblasts. It also linked with FAK phosphorylation especially p-FAK (Y925) (P<0.05). When GM6001 (a broad-spectrum MMP inhibitor) was added with HGF, HGF-induced apptosis was significantly decreased. It was suggested that increased activities of MMPs underlie the major mechanism of HGF mediated anoikis induced apoptosis. The present study demonstrated that HGF elicited myofibroblast anoikis. Activation of MMPs in fibrotic kidney might be considered as a target to attenuate the progression of CKD.

Abstract 76: Effects of Long-term Angiotensin-II Infusion on Cardiac and Renal Fibrosis are Blunted in TNFR1-deficient Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Magdalena Mayr ◽  
Clemens Duerrschmid ◽  
Dorellyn B Lee ◽  
Guillermo Medrano ◽  
George E Taffet ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Systolic Blood Pressure ◽  
Renal Fibrosis ◽  
Cardiac Fibrosis ◽  
Ang Ii ◽  
Fibrotic Response ◽  
2D Echocardiography ◽  
Collagen Iii

Background: Brief systemic infusion of Angiotensin-II (Ang-II) to wild-type (WT) mice initiates the development of cardiac interstitial fibrosis. Genetic deletion of tumor necrosis factor receptor 1 (TNFR1) obviates this development and concurrently inhibits Ang-II-induced cardiac remodeling and dysfunction. We now investigated long-term effects of Ang-II on the heart, kidney, and cardiorenal function. Methods: WT and TNFR1-KO mice were infused with 1.5 ug/kg/min Ang-II for 1 and 6 weeks (no uninephrectomy or high-salt diet). Heart, kidney, and serum were isolated and evaluated by histology, cytometry, qPCR, and ELISA techniques. Cardiac function was determined by 2D-echocardiography, systolic blood pressure by tail-cuff plethysmography. Results: Brief infusion of Ang-II to WT mice did not evoke a fibrotic response in the kidney. However, after 6 weeks, WT kidneys developed minimal, but significant interstitial collagen deposition which was supported by upregulation of collagen-I, collagen-III, and alpha-smooth muscle actin gene activation. This fibrotic development was associated with the appearance of myeloid fibroblast precursors, pro-inflammatory M1 and pro-fibrotic M2 cells, and myofibroblasts. Transcriptional expression of pro-inflammatory and pro-fibrotic genes was also increased. These changes were not seen in Ang-II-infused TNFR1-KO kidneys. In WT hearts, despite the disappearance of myeloid cells, cardiac fibrosis persisted throughout the 6-week infusion. WT hearts developed clear evidence of accelerated cardiac hypertrophy and remodeling associated with impaired systolic function. Again, these changes were not seen in Ang-II-infused TNFR1-KO hearts. By contrast, both WT and TNFR1-KO mice responded identically with similar elevations of systolic blood pressure, and serum blood urea nitrogen and creatinine levels. Conclusions: Ang-II-infusion induced an immediate fibrotic response in the heart while fibrosis in the kidney developed slowly. The cardiac fibrosis was accompanied by progressive adverse remodeling and worsening of function over time. TNFR1-KO mice were protected from the Ang-II-induced cardiac and renal fibrosis, despite similar increases in blood pressure and renal dysfunction.

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.

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.

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.

scholarly journals Cardiac steatosis potentiates angiotensin II effects in the heart

2015 ◽  
Vol 308 (4) ◽  
pp. H339-H350 ◽  
Author(s):  
Denis J. Glenn ◽  
Michelle C. Cardema ◽  
Wei Ni ◽  
Yan Zhang ◽  
Yerem Yeghiazarians ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Neutralizing Antibodies ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Systolic Function ◽  
Diabetic Patients ◽  
Type I ◽  
Ang Ii ◽  
Obesity And Diabetes ◽  
Lipid Species

Lipid accumulation in the heart is associated with obesity and diabetes and may play an important role in the pathogenesis of heart failure. The renin-angiotensin system is also thought to contribute to cardiovascular morbidity in obese and diabetic patients. We hypothesized that the presence of lipid within the myocyte might potentiate the cardiomyopathic effects of ANG II in the cardiac diacylglycerol acyl transferase 1 (DGAT1) transgenic mouse model of myocyte steatosis. Treatment with ANG II resulted in a similar increase in blood pressure in both nontransgenic and DGAT1 transgenic mice. However, ANG II in DGAT1 transgenic mice resulted in a marked increase in interstitial fibrosis and a reduction in systolic function compared with nontransgenic littermates. Lipidomic analysis revealed that >20% of lipid species were significantly altered between nontransgenic and DGAT1 transgenic animals, whereas 3% were responsive to ANG II administration. ROS were also increased by ANG II in DGAT1 transgenic hearts. ANG II treatment resulted in increased expression of transforming growth factor (TGF)-β2and the type I TGF-β receptor as well as increased phosphorylation of Smad2 in DGAT1 transgenic hearts. Injection of neutralizing antibodies to TGF-β resulted in a reduction in fibrosis in DGAT1 transgenic hearts treated with ANG II. These results suggest that myocyte steatosis amplifies the fibrotic effects of ANG II through mechanisms that involve activation of TGF-β signaling and increased production of ROS.

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