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 beta (TGF beta) 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 TGF beta and activation of its downstream in Col4a3(-/-) mice were attenuated by olmesartan in Col4a3(-/-) mice. Intriguingly, TGF beta expression was preferentially upregulated in damaged tubular epithelial cells in Col4a3(-/-) mice. Concurrent upregulation of TNF alpha-converting enzyme and downregulation of ACE2 suggested RAS activation in Col4a3(-/-) mice, which was prevented by olmesartan. Mechanistically, olmesartan suppressed TGF beta-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-TGF beta feedback loop to counterbalance intrarenal RAS activation.