Tamoxifen ameliorates obstructive nephropathy through Src and the PI3K/Akt/mTOR pathway

Area of Science:

• Nephrology
• Pharmacology
• Cell Biology

Background:

• Tubulointerstitial fibrosis is a common endpoint for chronic kidney diseases.
• Tamoxifen, a selective estrogen receptor modulator, has shown potential in attenuating renal fibrosis.
• The precise mechanisms by which tamoxifen affects non-canonical TGF-β signaling in renal fibrosis are not fully understood.

Purpose of the Study:

• To investigate the role of tamoxifen in ameliorating renal fibrosis induced by unilateral ureteral obstruction (UUO) in rats.
• To elucidate the signaling pathways, including Src, PI3K/Akt, and mTOR/p70S6K, involved in tamoxifen's anti-fibrotic effects.
• To confirm the involvement of estrogen receptor-alpha (ER-α) in tamoxifen's therapeutic action.

Main Methods:

• Renal fibrosis was induced in rats via UUO, followed by tamoxifen administration.
• HK-2 cells were treated with tamoxifen and TGF-β1 to study cellular responses.
• Selective ER down-regulator ICI and ER-α silencing were employed to assess ER-α's role.
• Western blotting was used to analyze protein expression and phosphorylation levels of key signaling molecules.

Main Results:

• Tamoxifen treatment significantly reduced markers of renal fibrosis, including α-SMA, fibronectin, and CTGF, in UUO rats.
• Tamoxifen suppressed the phosphorylation of Src, PI3K, Akt, mTOR, and p70S6K in both animal models and HK-2 cells.
• The anti-fibrotic effects of tamoxifen were reversed by ICI treatment and ER-α silencing, highlighting ER-α's crucial role.
• Inhibition of PI3K/Akt and mTOR/p70S6K pathways was observed when HK-2 cells were co-treated with tamoxifen and a Src kinase inhibitor (PP1).

Conclusions:

• Tamoxifen exerts anti-fibrotic effects by suppressing Src kinase activity through ER-α.
• This suppression subsequently inhibits the PI3K/Akt and mTOR/p70S6K signaling pathways, crucial in renal fibrosis.
• Tamoxifen represents a promising novel therapeutic agent for preventing and treating renal fibrosis.