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 alpha receptor-1 (TNFR1) obviates this development and concurrently inhibits Ang-II-induced cardiac hypertrophy and remodeling. Ang-II is also a major regulator of kidney function, but the contribution of TNFR1 signaling to renal health is unclear. Therefore, we now investigated the long-term effects of Ang-II and TNFR1 signaling on the heart, kidney, and cardiorenal function. Methods: WT and TNFR1-knockout (TNFR1-KO) mice were infused with 1.5 g/kg/min Ang-II for 1 and 6 weeks. Heart, kidney, and serum were isolated and evaluated by histologic, immunohistochemical, cytometric, quantitative PCR, and enzymatic measurement methods. ^Cardiac remodeling and function was determined by 2D-directed M-mode echocardiography and Doppler ultrasound and systolic blood pressure by tail-cuff plethysmography. Results: In WT hearts, despite the disappearance of myeloid cells, cardiac fibrosis persisted throughout the 6- week infusion of Ang-II. At this time point, WT hearts generally maintained systolic and diastolic function, however, they developed clear evidence of accelerated cardiac hypertrophy and remodeling. These changes were less prominent in Ang-II-infused TNFR1-KO hearts. 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. This finding was supported by upregulation of collagen type I and III, and -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. By contrast, both WT and TNFR1-KO mice responded identically with similar elevations of systolic blood pressure, serum blood urea nitrogen, and serum creatinine levels. Conclusion: Ang-II-infusion induced an immediate fibrotic response in the heart while fibrosis in the kidney developed slowly; both were initiated by chemokine-driven uptake of myeloid fibroblast precursor cells. The cardiac fibrosis was accompanied by progressive adverse remodeling. TNFR1-KO mice were protected from the Ang-IIinduced cardiac and renal fibrosis, despite similar increases in blood pressure and renal dysfunction.