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논문분류	춘계학술대회 초록집
제목	Tamoxifen attenuates renal fibrosis through Src kinase in obstructive nephropathy in rats
저자	Chang Seong Kim, Hong Sang Choi, Ha Yeon Kim, In Jin Kim, Eun Hui Bae, Seong Kwon Ma, Soo Wan Kim
출판정보	2018; 2018(1):
키워드	Tamoxifen \| Kidney \| fibrosis \| Scr \| phosphoinositide 3-kinase
초록	Objectives: Tubulointerstitial fibrosis is the final pathway of chronic progressive kidney diseases. Tamoxifen, a selective estrogen receptor (ER) modulator, attenuates renal fibrosis by regulating transforming growth factor (TGF)-β/Smad signaling in a mouse model. Src kinase and phosphoinositide 3-kinase (PI3K)/Akt pathways play critical roles in the pathogenesis of renal fibrosis. However, non-canonical TGF-β1/Smad signaling in renal fibrosis after treatment with tamoxifen remain unclear. Methods: Renal fibrosis was induced by 14 days of unilateral ureteral obstruction (UUO) in male Sprague-Dawley rats. Tamoxifen (10 mg/kg) was given by oral gavage after UUO. We also treated human proximal tubular epithelial (HK-2) cells with tamoxifen in the presence or absence of TGF-β1 (2 ng/mL). The ER-α antagonist, ICI (5 μM), and ER-α receptor siRNA were used to examine the effects of tamoxifen treatment on ER-α-mediated TGF-β1-stimulated renal fibrosis. Results: Tamoxifen treatment ameliorated UUO-induced renal fibrosis as shown by decreased expression of α-smooth muscle actin (SMA), fibronectin, and connective tissue growth factor (CTGF). Phosphorylation of Src (Tyr 416), PI3K/Akt, and mammalian target of rapamycin (mTOR)/p70S6K proteins was also significantly decreased in tamoxifen- compared to vehicle-treated UUO kidneys. Tamoxifen dose-dependently suppressed TGF-β1-induced expression of α-SMA and CTGF proteins, and phosphorylation of Src, PI3K/Akt, and mTOR/p70S6K in HK-2 cells in vitro. These antifibrotic effects were blunted by treatment with ICI and silencing ER-α with siRNA. Moreover, potent reduced renal fibrosis and inhibition of PI3K/Akt and mTOR/p70S6K were observed in HK-2 cells co-treated with PP1 (an Src kinase inhibitor) and tamoxifen. Conclusions: Tamoxifen-induced antifibrotic effects are associated with the suppression of Src kinase via ER-α, followed by inhibition of phosphorylation of PI3K/Akt and mTOR/p70S6K signaling pathways.
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