title: TNF/Ang-II synergy is obligate for fibroinflammatory pathology, but not for changes in cardiorenal function.
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.
authors.affiliation: Division of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Mayr
authors.affiliation: Division of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Clemens
authors.initials: C
authors.lastname: Duerrschmid
authors.affiliation: Division of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Medrano
authors.affiliation: Division of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: George E
authors.initials: GE
authors.lastname: Taffet
authors.affiliation: Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.affiliation: Division of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas shaudek@bcm.edu.
authors.forename: Sandra B
authors.initials: SB
authors.lastname: Haudek
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II
keywords: Angiotensin‐II; fibrosis; heart; inflammation; kidney; tumor necrosis factor