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.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…Prevalence of M1 and M2 was associated with a proinflammatory and profibrotic cytokine milieu, respectively, and evidence was reported that formation of M2 cells was dependent on production of TNF-␣ by M1 cells (247). However, the exact identity and function of the myeloid fibrocytes in ANG II-induced cardiac fibrosis is unclear given the previously discussed results of lineage tracing and the relative transient presence of the myeloid fibrocytes in the heart (672).…”

Complexity of TNF-α Signaling in Heart Disease

“…Similar data were obtained in another model of hypertrophic cardiomyopathy. In an angiotensin II osmotic minipump model, Tnfa −/− and Tnfrsf1a −/− mice showed significantly attenuated phenotype [ 126 , 127 ]. In-depth analysis demonstrated reduced immunofibrotic changes in the myocardium of Tnfrsf1a −/− mice, but there was no protective effect on diastolic dysfunction in this model [ 127 ].…”

“…In an angiotensin II osmotic minipump model, Tnfa −/− and Tnfrsf1a −/− mice showed significantly attenuated phenotype [ 126 , 127 ]. In-depth analysis demonstrated reduced immunofibrotic changes in the myocardium of Tnfrsf1a −/− mice, but there was no protective effect on diastolic dysfunction in this model [ 127 ]. In contrast, Tnfrsf1b −/− mice receiving angiotensin II infusion developed fibrosis and showed only slight changes in expression of pro-fibrotic genes [ 128 ].…”

Inflammation and Trajectory of Renal Function in Community‐Dwelling Older Adults

“…Although that study did not measure inflammatory biomarkers, aging is associated with the development of inflammatory states. Another study demonstrated that angiotensin‐II infusion in mice introduced a fibroinflammatory response that is followed by kidney tubulointerstitial collagen deposition mediated through the TNF‐R1 signaling pathway and speculated that TNF α ‐R1 triggers collagen deposition . A significant association between lipocalin 2 in mesangial cells and sTNF α ‐R2 levels and impaired kidney function has also been reported .…”