Takehito Kondo

APPLICATION OF AN ADENOVIRAL VECTOR ENCODING SOLUBLE TRANSFORMING GROWTH FACTOR‐β TYPE II RECEPTOR TO THE TREATMENT OF DIABETIC NEPHROPATHY IN MICE

1 In the present study, we examined the effects of inhibiting transforming growth factor (TGF)‐β in a mouse model of diabetic nephropathy. 2 An adenovirus harbouring the gene encoding soluble TGF‐β type II receptor (Ad.CAG‐sTβRII), a competitive inhibitor of TGF‐β, was injected into hindlimb muscles (systemic delivery) of mice 5 weeks after the induction of diabetes with streptozotocin. The control group was injected with an adenovirus encoding the LacZ gene (Ad‐LacZ). 3 Five weeks after administration, anti‐TGF‐β gene therapy was found to have had no effect on renal function, albuminuria or glucose metabolism in mice with diabetic nephropathy. Nonetheless, this gene therapy did significantly reduce fibrosis in both glomeruli and renal tubules. These effects were accompanied by attenuation of the increased expression of α‐smooth muscle actin normally seen in kidneys of diabetic mice and better preservation of glomerular cell numbers, although the thickness of the glomerular capillary basement membrane was unchanged. The plasma concentration of soluble TGF‐β type II receptor peaked on Day 7 after treatment, but was undetectable by Day 14. Moreover, a second treatment with Ad.CAG‐sTβRII failed to prolong the interval of gene product expression in the blood. 4 The present anti‐TGF‐β gene therapy showed a significant antifibrotic effect in a model of diabetic nephropathy, but failed to improve renal function. The inadequacy of the observed effect is likely due to the relatively short interval of gene product expression. This problem will have to be overcome if gene therapies for slowly progressing diseases, like diabetic nephropathy, are to be realised.