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Histone deacetylases have been a target of therapy for organ fibrosis. Here, we report the protective effect of CG200745 (CG), a novel histone deacetylase inhibitor, on tubulointerstitial fibrosis in Col4a3−/− mice, a murine model of Alport syndrome. Morphological analyses revealed CG treatment markedly alleviated kidney fibrosis in Col4a3−/− mice at the age of 7 weeks. CG prevented the activation of transforming growth factor β (TGFβ) and its downstream SMAD signaling in the kidney of Col4a3−/− mice. As critical upstream regulators of TGFβ signaling, immunoblotting of whole kidney lysate of Col4a3−/− mice reveled that intra-renal renin–angiotensin system (RAS) was activated with concurrent upregulation of inflammation and apoptosis, which were effectively suppressed by CG treatment. CG suppressed both activation of RAS and up-regulation of TGFβ signals in angiotensin II-stimulated HK-2 cells, a human kidney proximal tubular epithelial cell line. CG inhibited activation of TGFβ-driven signals and fibrosis in NRK-49F cells, a rat kidney fibroblast cell line, under angiotensin II-rich conditions. Collectively, CG was found to be effective both in proximal tubular epithelial cells by inhibiting local RAS and TGFβ signaling activation, as well as in fibroblasts by blocking their transition to myofibroblasts, attenuating renal fibrosis in a murine model of Alport syndrome. [ABSTRACT FROM AUTHOR]

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]