Abstract
Angiotensin-II (Ang-II) infusion is associated with the development of interstitial fibrosis in both heart and kidney as a result of chemokine-dependent uptake of monocytes and subsequent development of myeloid fibroblasts. This study emphasizes on the synergistic role of tumor necrosis factor (TNF) on the time course of Ang-II-induced fibrosis and inflammation in heart and kidney. In wild-type (WT) hearts, Ang-II-induced fibrosis peaked within 1 week of infusion and remained stable over a 6-week period, while the myeloid fibroblasts disappeared; TNF receptor-1-knockout (TNFR1-KO) hearts did not develop a myeloid response or cardiac fibrosis during this time. WT hearts developed more accelerated cardiac hypertrophy and remodeling than TNFR1-KO. In the kidney, 1-week Ang-II infusion did not evoke a fibrotic response; however, after 6 weeks, WT kidneys displayed modest but significant tubulointerstitial collagen deposition associated with the appearance of myeloid cells and profibrotic gene activation. Renal fibrosis was not seen in Ang-II-infused TNFR1-KO. By contrast, while hypertension increased and cardiac function decreased more slowly in TNFR1-KO than WT, they were equivalently abnormal at 6 weeks. Similarly, serum markers for renal dysfunction were not different after 6 weeks. In conclusion, Ang-II infusion initiated fibroinflammatory responses with different time courses in heart and kidney, both requiring TNFR1 signaling, and both associated with monocyte-derived myeloid fibroblasts. TNFR1 deletion obviated the fibroinflammatory effects of Ang-II, but did not alter changes in blood pressure and cardiorenal function after 6 weeks. Thus, the synergy of TNF with Ang-II targets the fibroinflammatory component of Ang-II signaling.
Original language | English (US) |
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Article number | e12765 |
Journal | Physiological Reports |
Volume | 4 |
Issue number | 8 |
DOIs | |
State | Published - Apr 1 2016 |
Keywords
- Angiotensin-II
- Fibrosis
- Heart
- Inflammation
- Kidney
- Tumor necrosis factor
ASJC Scopus subject areas
- Physiology
- Physiology (medical)