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Poster Abstract PresentationsSession Title: Poster Session 1

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

Magdalena Mayr, Clemens Duerrschmid, Dorellyn B Lee, Guillermo Medrano, George E Taffet, Mark L Entman, Sandra B Haudek
Circulation Research. 2015;117:A76
Magdalena Mayr
Baylor College of Medicine, Houston, TX
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Clemens Duerrschmid
Baylor College of Medicine, Houston, TX
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Dorellyn B Lee
Baylor College of Medicine, Houston, TX
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Guillermo Medrano
Baylor College of Medicine, Houston, TX
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George E Taffet
Baylor College of Medicine, Houston, TX
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Mark L Entman
Baylor College of Medicine, Houston, TX
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Sandra B Haudek
Baylor College of Medicine, Houston, TX
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Abstract

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.

  • Fibrosis
  • Angiotensin-II
  • cardio-renal
  • Author Disclosures: M. Mayr: None. C. Duerrschmid: None. D.B. Lee: None. G. Medrano: None. G.E. Taffet: None. M.L. Entman: None. S.B. Haudek: None.

  • This research has received full or partial funding support from the American Heart Association, National Center.

  • © 2015 by American Heart Association, Inc.
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Circulation Research
July 17, 2015, Volume 117, Issue Suppl 1
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    Abstract 76: Effects of Long-term Angiotensin-II Infusion on Cardiac and Renal Fibrosis are Blunted in TNFR1-deficient Mice
    Magdalena Mayr, Clemens Duerrschmid, Dorellyn B Lee, Guillermo Medrano, George E Taffet, Mark L Entman and Sandra B Haudek
    Circulation Research. 2015;117:A76, originally published October 21, 2015

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    Abstract 76: Effects of Long-term Angiotensin-II Infusion on Cardiac and Renal Fibrosis are Blunted in TNFR1-deficient Mice
    Magdalena Mayr, Clemens Duerrschmid, Dorellyn B Lee, Guillermo Medrano, George E Taffet, Mark L Entman and Sandra B Haudek
    Circulation Research. 2015;117:A76, originally published October 21, 2015
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