Adenovirus-mediated Gene Therapy of Uteroglobin Protects the Experimental Glomerulonephritis in Mice

Kim, Hyun Lee; Yang, Seung Hee; Sung, Eun Young; Lee, Jung Eun; Lee, Dong Sup; Chung, Jong Hoon; Kim, Yon Su

Abstract

PURPOSE
Uteroglobin (UG), steroid inducible cytokine-like protein, has potent anti-inflammatory and immunomodulatory action. It is secreted by the mucosal epithelia of virtually all mammals. The aims of this study were to investigate the efficacy of recombinant adenovirus carrying uteroglobin (AdCMV-UG) in prevention and treatment of glomerulonephritis (GN) in mice. METHODS: The AdCMV-UG was created by inserting the uteroglobin cDNA into the pAdTrack- CMV vector and was transfected into the 293 cells through liposome mediated vehicles. AdCMV-UG was injected direct to the both kidneys of 20 mice. In control groups (disease controls), 13 mice received adenoviral vector with GFP and another 11 mice received PBS only. After 5days of viral injection, GN was induced by repetitive intravenous injection of 3.0 mg rabbit anti-GBM Ab to the pretreated mice (C57/B6). Histological and biochemical changes were evaluated 7 and 14 days after injection of anti-GBM Ab. RESULTS: UG was expressed in the renal tissues and mesangial cells infected with the infection of AdCMV-UG. Pretreatment with AdCMV-UG attenuated the cellular crescent formation 7 days after induction of GN when compared to AdCMV-GFP, PBS only. We also observed reduced mesangial matrix expansion in mice treated with adenovirus carrying UG. Proteinuria was significantly reduced in the mice treated with adenovirus carrying UG when compared with disease control mice (AdCMV-UG 102.2+/-20.97, AdCMV-GFP 170.6+/-41.77, and PBS 169.8+/-55.67, respectively p<0.05 mg/mg). However, at 14 days after anti-GBM Ab injection (total 19 days), there was no significant difference in the amounts of prot einuria and morphologic findings between pretreated and disease control groups. CONCLUSION: Adenoviral mediated gene transfer is an effective way of gene delivery. Locally expressed uteroglobin attenuated the severity of glomerulonephritis induced by anti-GBM antibody, although it was transient. Gene therapy using uteroglobin may be constituted for the treatment of human diseases such as chronic GN.