Renal expression of fibrotic matrix proteins and of transforming growth factor-beta (TGF-beta) isoforms in TGF-beta transgenic mice

Renal pathology in mice that are transgenic for the murine albumin enhancer /promoter linked to a full-length porcine transforming growth factor-beta 1 (TGF-beta 1) gene has been described previously. In these mice, transgene expression is limited to the liver and the plasma level of TGF-beta is incr eased. The earliest renal pathologic change is glomerulosclerosis, at 3 wk of age, and this is followed by tubulointerstitial fibrosis. In this study, it was hypothesized that circulating TGF-beta 1 increases renal extracellu lar matrix accumulation and activates local TGF-beta gene expression. Immun ostaining at 5 wk revealed increased amounts of collagen I and II within th e mesangium, glomerular capillary loops, and interstitium, while the amount of collagen IV was normal. Similarly, Northern analysis showed increased e xpression of mRNA encoding collagen I and III, as well as biglycan and deco rin, while the expression of collagen IV was unchanged. These changes began as early as 1 wk of age, a time before the appearance of glomerulosclerosi s. To evaluate matrix degradation, collagenase IV activity was evaluated by gelatin zymography and an increase in matrix metalloproteinase-2 was found . Finally, the production of tissue inhibitors of metalloproteinase was eva luated. Tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA was increased 18-fold, while TIMP-2 and TIMP-3 were unchanged. In 2-wk-old transgenic ki dney, local expression of TGF-beta 1, beta 2, and beta 3 protein was simila r to wild-type mice. In 5-wk-old transgenic mice, TGF-beta 1 and beta 2 pro tein was present in increased amounts within glomeruli, and renal TGF-beta 1 mRNA was increased threefold. It is concluded that elevated levels of cir culating TGF-beta 1 may act on the kidney to increase matrix protein produc tion and decrease matrix remodeling. Only after glomerulosclerosis is estab lished does local glomerular overproduction of TGF-beta become manifest.