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

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.

• Authors: Yoshifumi Hamasaki, Kent Doi, Koji Okamoto, Hideaki Ijichi, George Seki, Rui Maeda-Mamiya, Toshiro Fujita, Eisei Noiri
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 92 Issue 8 Pg. 1161-70 (Aug 2012) ISSN: 1530-0307 [Electronic] United States
• PMID: 22525429 (Publication Type: Journal Article)

Chemical References

• Adaptor Proteins, Signal Transducing
• Bone Morphogenetic Protein 7
• Bone Morphogenetic Proteins
• Homeodomain Proteins
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Protective Agents
• Sostdc1 protein, mouse
• homeobox protein HOXA13
• Simvastatin

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Bone Morphogenetic Protein 7 (metabolism)
• Bone Morphogenetic Proteins (genetics, metabolism)
• Cell Line
• Dogs
• Female
• Fibrosis (drug therapy, metabolism)
• Homeodomain Proteins (genetics, metabolism)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Kidney Diseases (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Models, Biological
• Polymerase Chain Reaction
• Promoter Regions, Genetic
• Protective Agents (pharmacology)
• Signal Transduction
• Simvastatin (pharmacology)