Blockade of TGF-β action ameliorates renal dysfunction and histologic progression in anti-GBM nephritis

Background. We tested whether the entire soluble extracellular domain of the human transforming growth factor-P (TGF-beta) type II receptor, fused to the Fc portion of human immunoglobulin G (IgG1) (Tbeta-ExR) and expressed in skeletal muscles by adenovirus-mediated gene transfer (AdTbeta-ExR), can ameliorate renal dysfunction and histologic progression in a rat experimental anti-glomerular basement membrane (GBM) nephritis. Methods. Anti-GBM nephritis was induced in Wistar Kyoto rats by an intravenous injection of anti-rat glomerular basement membrane (GBM) sera. At day 1 (24 hours after induction), AdTbeta-ExR (1 X 10(9) pfu/mL) was injected into the femoral muscle in the treatment group, and an adenovirus vector-expressing bacterial P-galactosidase (AdLacZ) was injected into the control group. Then, clinical and histologic changes were examined for 3 weeks after the induction of anti-GBM nephritis. Results. Tbeta-ExR was detected in the serum at day 7, but the serum concentration of Tbeta-ExR had decreased below the detectable level by day 14. Although blood pressure and the degree of proteinuria were similar in both groups, the deterioration of renal function was significantly blunted in the treatment group. Crescent formation and interstitial fibrosis were also ameliorated in the treatment group. These histologic improvements were accompanied by the decreased interstitial infiltration of macrophages and the decreased a-smooth muscle actin (alpha-SMA)-positive cells in the glomeruli and the interstitium. Conclusion. This study demonstrated for the first time that the blockade of TGF-beta action by AdTbeta-ExR in the early stage of anti-GBM nephritis ameliorates the clinical and histologic progression. In addition, this study shed light on the development of a specific gene therapy for human crescentic glomerulonephritis.