Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFβ.

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 mice, a murine model of experimental AS. Morphology analyses revealed amelioration of kidney fibrosis in mice by olmesartan treatment. Upregulation of TGFβ and activation of its downstream in mice were attenuated by olmesartan in mice. Intriguingly, TGFβ expression was preferentially upregulated in damaged tubular epithelial cells in mice. Concurrent upregulation of TNFα-converting enzyme and downregulation of ACE2 suggested RAS activation in 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.