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<p>Statins act as antifibrotic agents but their mechanism is unclear. Therefore, we aimed to evaluate the antifibrotic effects of rosuvastatin in a chronic kidney fibrosis model in vivo and transforming growth factor-β1 (TGF-β1)-stimulated Madin-Darby canine kidney (MDCK) cells in vitro. Mice with unilateral ischemic reperfusion injury and contralateral nephrectomy (uIRIx) were administered vehicle or rosuvastatin (10&#xa0;mg/kg/day by oral gavage) for four weeks and kidney fibrosis markers were analyzed. Moreover, control and homeobox protein Hox-A13 (HOXA13) knocked-down MDCK cells were stimulated with TGF-β1 (5&#xa0;ng/ml) and then treated with rosuvastatin. The uIRIx mice developed severe tubulointerstitial fibrosis with increased α-smooth muscle actin (α-SMA), collagen I and uterine sensitization-associated gene-1 (USAG-1) expression, but rosuvastatin therapy attenuated these expression and improved fibrosis. Rosuvastatin also reduced Smad3 phosphorylation and increased Smad1/5/9 phosphorylation, both associated with bone morphogenetic protein-7 (BMP-7) signaling. TGF-β1-stimulated MDCK cells exhibited increased α-SMA, fibronectin, vimentin, and collagen 1 expression, which rosuvastatin reversed. In addition, TGF-β1-stimulated MDCK cells demonstrated increased USAG-1 expression without changes in BMP-7 expression. Gene knockdown using HOXA13 siRNA suggested rosuvastatin decreased USAG-1 expression by increasing HOXA13 expression. Our results demonstrate that rosuvastatin inhibits kidney fibrosis by activating BMP-7 signaling via upregulation of HOXA13 and downregulation of USAG-1.</p>

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Rosuvastatin attenuates tubulointerstitial fibrosis by targeting the HOXA13 USAG1 BMP7 pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Donghwan Oh,
  • Hyo Jeong Kim,
  • Seok-hyung Kim,
  • Soo Hyun Kim,
  • Tae Yeon Kim,
  • Hoon Young Choi,
  • Hyunwook Kim,
  • Hyung Jong Kim,
  • Hyeong Cheon Park

摘要

Statins act as antifibrotic agents but their mechanism is unclear. Therefore, we aimed to evaluate the antifibrotic effects of rosuvastatin in a chronic kidney fibrosis model in vivo and transforming growth factor-β1 (TGF-β1)-stimulated Madin-Darby canine kidney (MDCK) cells in vitro. Mice with unilateral ischemic reperfusion injury and contralateral nephrectomy (uIRIx) were administered vehicle or rosuvastatin (10 mg/kg/day by oral gavage) for four weeks and kidney fibrosis markers were analyzed. Moreover, control and homeobox protein Hox-A13 (HOXA13) knocked-down MDCK cells were stimulated with TGF-β1 (5 ng/ml) and then treated with rosuvastatin. The uIRIx mice developed severe tubulointerstitial fibrosis with increased α-smooth muscle actin (α-SMA), collagen I and uterine sensitization-associated gene-1 (USAG-1) expression, but rosuvastatin therapy attenuated these expression and improved fibrosis. Rosuvastatin also reduced Smad3 phosphorylation and increased Smad1/5/9 phosphorylation, both associated with bone morphogenetic protein-7 (BMP-7) signaling. TGF-β1-stimulated MDCK cells exhibited increased α-SMA, fibronectin, vimentin, and collagen 1 expression, which rosuvastatin reversed. In addition, TGF-β1-stimulated MDCK cells demonstrated increased USAG-1 expression without changes in BMP-7 expression. Gene knockdown using HOXA13 siRNA suggested rosuvastatin decreased USAG-1 expression by increasing HOXA13 expression. Our results demonstrate that rosuvastatin inhibits kidney fibrosis by activating BMP-7 signaling via upregulation of HOXA13 and downregulation of USAG-1.