3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin ameliorates renal fibrosis through HOXA13-USAG-1 pathway

Yoshifumi Hamasaki, Kent Doi, Koji Okamoto, Hideaki Ijichi, George Seki, Rui Maeda-Mamiya, Toshiro Fujita, Eisei Noiri

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Epidemiological data have suggested that 3-hydroxy-3-methylglutaryl- coenzyme A reductase inhibitors (statins) prevent the progression of chronic kidney diseases (CKDs), whereas the precise mechanism explaining in vitro to in vivo is missing. This study is aimed at exploring a new mechanism of action by statins on renal fibrosis, a hallmark of CKD, using mouse renal fibrosis model in vivo and Madin-Darby canine kidney (MDCK) cells expressing USAG-1 in vitro. C57/BL6 mice fed a 0.2% adenine-containing diet for 4 weeks developed renal dysfunction accompanied with severe tubulointerstitial fibrosis. Subsequent simvastatin (SIM) treatment (50 mg/kg per day) for 2 weeks significantly suppressed fibrosis progression. We found that SIM enhanced bone morphogenetic protein-7 (BMP-7)-mediated anti-fibrotic signaling with the reduced expression of uterine sensitization-associated gene-1 (USAG-1), a BMP-7 antagonist produced by renal distal tubular epithelial cells. Therefore, MDCK cells were incubated with transforming growth factor-Β1 and showed increased expression of USAG-1 and α-smooth muscle actin; SIM significantly reduced them. SIM significantly increased E-cadherin expression. Gene knockdown experiments using MDCK suggested that homeobox protein Hox-A13 (HOXA13) played a suppressive role in the USAG-1 gene and thus SIM reduced USAG-1 by increasing HOXA13 expression. The data from our study demonstrate that SIM, one of statins, contributes to prevent the progression of renal fibrosis by upregulating BMP-7-mediated anti-fibrotic signaling and that one aspect of crucial efficacies is achieved by regulating HOXA13 and USAG-1. HOXA13-USAG-1 pathway is a newly identified mechanism in renal fibrosis and will be a new therapeutic target for preventing renal fibrosis progression in CKDs.

Original languageEnglish
Pages (from-to)1161-1170
Number of pages10
JournalLaboratory Investigation
Volume92
Issue number8
DOIs
Publication statusPublished - 2012 Aug
Externally publishedYes

Keywords

  • BMP-7
  • HOXA13
  • TGF-β1
  • USAG-1
  • statin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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