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Despite the wide use of angiotensin II receptor blockers in the treatment of Alport syndrome (AS), the mechanism as to how angiotensin II receptor blockers prevent interstitial fibrosis remains unclear. Here, we report that treatment of olmesartan effectively targets the feedback loop between the renin–angiotensin system (RAS) and transforming growth factor β (TGFβ) signals in tubular epithelial cells and preserves renal angiotensin-converting enzyme 2 (ACE2) expression in the kidney of Col4a3–/– mice, a murine model of experimental AS. Morphology analyses revealed amelioration of kidney fibrosis in Col4a3–/– mice by olmesartan treatment. Upregulation of TGFβ and activation of its downstream in Col4a3–/– mice were attenuated by olmesartan in Col4a3–/– mice. Intriguingly, TGFβ expression was preferentially upregulated in damaged tubular epithelial cells in Col4a3–/– mice. Concurrent upregulation of TNFα-converting enzyme and downregulation of ACE2 suggested RAS activation in Col4a3–/– mice, which was prevented by olmesartan. Mechanistically, olmesartan suppressed TGFβ-induced RAS activation in tubular epithelial cells in vitro. Collectively, we concluded that olmesartan effectively suppresses the progression of tubulointerstitial fibrosis in AS by interrupting RAS-TGFβ feedback loop to counterbalance intrarenal RAS activation. [ABSTRACT FROM AUTHOR]