Basic studies for an effective therapy for Alport syndrome

2002 Fiscal Year Final Research Report Summary

• Project/Area Number: 13470159
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: NIIGATA UNIVERSITY
• Principal Investigator: UCHIYAMA Makoto NIIGATA UNIVERSITY Graduate School of Medical and Dental Sciences, Professor, 大学院・医歯学総合研究科, 教授 (80108050)
• Co-Investigator(Kenkyū-buntansha): SATOKATA Ichiro Graduate School of Medical and Dental Sciences, Professor, 大学院・医歯学総合研究科, 教授 (70170800)
• Project Period (FY): 2001 – 2002
• Keywords: Alport syndrome / cyclosporin A / enalapril / tenascin C / Col4a4 / gene therapy / electroporation / trancegenic mouse

Research Abstract

1. Study for the efficiency of drug therapy for Alport syndrome using Col4a4 deficient mice
Compared with untreated and mizoribine-treated groups, proteinuria and crescent formation were significantly reduced in cyclosporine A-treated and enalapril-treated groups. Furthermore, enalapril could significantly prolong the survival period of mutant mice, although cyclosporine A and mizoribine could not. Taken together, angiotensin converting enzyme inhibitor was thought to be effective in slowing down the progression towards renal failure in a mouse model of Alport syndrome.
2. Analysis of Col4a4, tenascin double deficient mice
Compared with Col4a4 deficient mice, proteinuria and survival period were significantly improved in Col4a4, tenascin double deficient mice. Elavation of tenascin gene expression observed at the glomerular basement membrane of Col4a4 deficient mice was thought to play a role for promote the pathological change of Alport syndrome.
3. Rescue study of the phenotype of Col4a4 deficient mice by Col4a4 transgenic mice
Col4a4 transgenic mice carrying CAG promoter and LacZ reporter gene were produced. The mice were mated with Col4a4 deficient mice. We are now examining whether the phenotype of Col4a4 deficient mice is rescued or not.
4. Study of gene therapy for Alport syndrome using electroporation
The plasmid pCAG- Col4a4-LacZ was electroporated into mouse kidneys by either abdominal aorta route or renal capsule route. Although efficiency of DNA introduction via abdominal aorta was very low, considerable number of cells in renal cortex were introduced the plasmid by electroporation from subcapsular route. The electroporation from subcapsular route may be available for gene therapy for Alport syndrome and other renal diseases.