title: Local delivery of matrix metalloproteinase gene prevents the onset of renal sclerosis in streptozotocin-induced diabetic mice.
abstract: The present study was undertaken to investigate whether matrix metalloproteinase (MMP) functions to prevent the occurrence of destructive fibrosis in progressive renal disease. As a sustained release carrier of plasmid DNA, biodegradable hydrogels and microspheres were formulated from cationized gelatin prepared through aminization. Plasmid DNA was released from the cationized gelatin hydrogels as a result of hydrogel degradation. A plasmid DNA including a cytomegalovirus promoter and human recombinant MMP-1 gene (pCMV-MMP) was constructed. Gelatin microspheres incorporating pCMV-MMP as well as phosphate-buffered saline (PBS) with or without pCMV-MMP were injected into the renal subcapsule of C57BL/6 mice, which were intraperitoneally injected with streptozotocin (STZ) to induce diabetes 7 days after operation. The mice were killed 4 weeks after STZ injection to sample their blood and kidneys for biochemical and histological examinations. An immunofluorescence study confirmed that MMP protein was expressed around the renal tissue injected with gelatin microspheres incorporating pCMV-MMP. When applied with cationized gelatin microspheres incorporating pCMV-MMP, the mice showed a level of blood urea nitrogen significantly lower than that of other groups. A reduced content of collagen in the kidneys of mice administered gelatin microspheres incorporating pCMV-MMP was histologically observed. Further, the hydroxyproline assay revealed a significantly decreased content of hydroxyproline in kidney. We conclude that sustained release of MMP-1 gene is a promising prophylactic trial for kidney fibrolysis and dysfunction in the STZ-induced diabetic mouse model.
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto, Japan.
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Aoyama
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kanematsu
authors.forename: Osamu
authors.initials: O
authors.lastname: Ogawa
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
mesh_terms: D000818:Animals; D003270:Contraceptive Agents; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D015918:Infusion Pumps, Implantable; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000008:administration & dosage*; D012598:Sclerosis; D013311:Streptozocin; D016896:Treatment Outcome
chemical_list: D003270:Contraceptive Agents; D013311:Streptozocin; D020781:Matrix Metalloproteinase 1