title: Nanotechnology and adeno-associated virus-based decorin gene therapy ameliorates peritoneal fibrosis.
abstract: Peritoneal dialysis (PD) is a life-sustaining therapy for end-stage renal disease (ESRD), used by 10-15% of the dialysis population worldwide. Peritoneal fibrosis (PF) is a known complication of long-term PD and frequently follows episodes of peritonitis, rendering the peritoneal membrane inadequate for dialysis. Transforming growth factor (TGF)-β is an inducer of fibrosis in several tissues and organs, and its overexpression has been correlated with PF. Animal models of peritonitis have shown an increase in expression of TGF-β in the peritoneal tissue. Decorin, a proteoglycan and component of the extracellular matrix, inactivates TGF-β, consequently reducing fibrosis in many tissues. Recently, gold nanoparticles (GNP) have been used for drug delivery in a variety of settings. In the present study, we tested the possibility that GNP-delivered decorin gene therapy ameliorates zymosan-mediated PF. We created a PF model using zymosan-induced peritonitis. Rats were treated with no decorin, GNP-decorin, or adeno-associated virus-decorin (AAV-decorin) and compared with controls. Tissue samples were then stained for Masson's trichrome, enface silver, and hematoxylin and eosin, and immunohistochemistry was carried out with antibodies to TGF-β1, α-smooth muscle actin (α-SMA), and VEGF. Animals which were treated with GNP-decorin and AAV-decorin gene therapy had significant reductions in PF compared with untreated animals. Compared with untreated animals, the treated animals had better preserved peritoneal mesothelial cell size, a significant decrease in peritoneal thickness, and decreased α-SMA. Quantitative PCR measurements showed a significant decrease in the peritoneal tissue levels of α-SMA, TGF-β, and VEGF in treated vs. untreated animals. This study shows that both GNP-delivered and AAV-mediated decorin gene therapies significantly decrease PF in vivo in a rodent model. This approach has important clinical translational potential in providing a therapeutic strategy to prevent PF in PD patients.
authors: Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri; Department of Medicine, Division of Nephrology, University of Missouri, Columbia, Missouri; chaudharyk@health.missouri.edu.
authors: Kunal
authors: K
authors: Chaudhary
authors: Department of Medicine, Division of Nephrology, University of Missouri, Columbia, Missouri;
authors: Harold
authors: H
authors: Moore
authors: Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri; Mason Eye Institute, School of Medicine, University of Missouri, Columbia, Missouri; and.
authors: Ashish
authors: A
authors: Tandon
authors: Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri; College of Veterinary Medicine, University of Missouri, Columbia, Missouri.
authors: Suneel
authors: S
authors: Gupta
authors: Department of Medicine, Division of Nephrology, University of Missouri, Columbia, Missouri;
authors: Ramesh
authors: R
authors: Khanna
authors: Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri; Mason Eye Institute, School of Medicine, University of Missouri, Columbia, Missouri; and College of Veterinary Medicine, University of Missouri, Columbia, Missouri.
authors: Rajiv R
authors: RR
authors: Mohan
mesh_terms: D000256:Adenoviridae; D000818:Animals; D058575:Decorin / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D053758:Nanoparticles; D056627:Peritoneal Fibrosis / Q000139:chemically induced / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015054:Zymosan
chemical_list: D058575:Decorin; D015054:Zymosan
keywords: decorin; fibrosis; nanoparticles; peritoneal