title: 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.affiliation: Department of Nephrology and Endocrinology, and Hemodialysis and Apheresis, University Hospital, University of Tokyo, Tokyo, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Hamasaki
authors.forename: Kent
authors.initials: K
authors.lastname: Doi
authors.forename: Koji
authors.initials: K
authors.lastname: Okamoto
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ijichi
authors.forename: George
authors.initials: G
authors.lastname: Seki
authors.forename: Rui
authors.initials: R
authors.lastname: Maeda-Mamiya
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Eisei
authors.initials: E
authors.lastname: Noiri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004285:Dogs; D005260:Female; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D020011:Protective Agents / Q000494:pharmacology; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D018398:Homeodomain Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020011:Protective Agents; C483887:Sostdc1 protein, mouse; C099959:homeobox protein HOXA13; D019821:Simvastatin