Abstract
Quercetin, a flavonoid found in a wide variety of plants and presented in human diet, displays promising potential in preventing kidney fibroblast activation. However, whether quercetin can ameliorate kidney fibrosis in mice with obstructive nephropathy and the underlying mechanisms remain to be further elucidated. In this study, we found that administration of quercetin could largely ameliorate kidney interstitial fibrosis and macrophage accumulation in the kidneys with obstructive nephropathy. MTORC1, mTORC2, β-catenin as well as Smad signaling were activated in the obstructive kidneys, whereas quercetin could markedly reduce their abundance except Smad3 phosphorylation. In cultured NRK-49F cells, quercetin could inhibit α-SMA and fibronectin (FN) expression induced by TGFβ1 treatment. MTORC1, mTORC2, β-catenin and Smad signaling pathways were stimulated by TGFβ1 at a time dependent manner. Similar to those findings in the obstructive kidneys, mTORC1, mTORC2 and β-catenin, but not Smad signaling pathways were remarkably blocked by quercetin treatment. Together, these results suggest that quercetin inhibits fibroblast activation and kidney fibrosis involving a combined inhibition of mTOR and β-catenin signaling transduction, which may act as a therapeutic candidate for patients with chronic kidney diseases.
Highlights
During the past decades, the mechanisms for kidney fibrosis have been deeply investigated, but few therapeutic strategies are available to efficiently halt the progression of interstitial fibrosis and chronic kidney diseases[5,6]
Given the critical role for mTOR and β -catenin signaling in mediating transforming growth factor-β 1 (TGFβ 1)-induced fibroblast activation and kidney fibrosis, we hypothesized that quercetin may suppress fibroblast activation and kidney fibrosis involving the suppression of these signaling pathways
To investigate the anti-fibrotic role of quercetin in the kidneys with obstructive nephropathy, we created a mice model with kidney fibrosis by unilateral ureter obstruction (UUO) in male CD1 mice, and quercetin was administered at 25 mg/kg.day intraperitoneally from 2 days before the operation
Summary
The mechanisms for kidney fibrosis have been deeply investigated, but few therapeutic strategies are available to efficiently halt the progression of interstitial fibrosis and chronic kidney diseases[5,6]. Accumulative evidences demonstrated that transforming growth factor-β 1 (TGFβ 1), a central mediator of fibrogenesis, may activate a panel of intracellular signaling pathways including Smad, β -catenin and mTOR1,18,19–21, and inhibiting such signaling pathways is protective against fibroblast activation and kidney fibrosis. Given the critical role for mTOR and β -catenin signaling in mediating TGFβ 1-induced fibroblast activation and kidney fibrosis, we hypothesized that quercetin may suppress fibroblast activation and kidney fibrosis involving the suppression of these signaling pathways. Similar to the in vivo studies, the activation of mTOR and β -catenin signaling pathways stimulated by TGFβ 1 treatment were blocked by quercetin, while Smad[3] phosphorylation remained unchanged
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