Open AccessTNF /Ang‐ II synergy is obligate for fibroinflammatory pathology, but not for changes in cardiorenal function
Author(s) -
Mayr Magdalena,
Duerrschmid Clemens,
Medrano Guillermo,
Taffet George E.,
Wang Yanlin,
Entman Mark L.,
Haudek Sandra B.
Publication year - 2016
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12765
Subject(s) - cardiorenal syndrome , fibrosis , medicine , endocrinology , kidney , angiotensin ii , renal function , cardiac fibrosis , receptor
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 ( TNFR 1‐ KO ) hearts did not develop a myeloid response or cardiac fibrosis during this time. WT hearts developed more accelerated cardiac hypertrophy and remodeling than TNFR 1‐ 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 TNFR 1‐ KO . By contrast, while hypertension increased and cardiac function decreased more slowly in TNFR 1‐ 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 TNFR 1 signaling, and both associated with monocyte‐derived myeloid fibroblasts. TNFR 1 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.