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

Miklos M. Mozes, Erwin P. Böttinger, Terry A. Jacot, Jeffrey B. Kopp

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

Renal pathology in mice that are transgenic for the murine albumin enhancer/promoter linked to a full-length porcine transforming growth factor- β1 (TGF-β1) gene has been described previously. In these mice, transgene expression is limited to the liver and the plasma level of TGF-β is increased. 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-β1 increases renal extracellular matrix accumulation and activates local TGF-β gene expression. Immunostaining at 5 wk revealed increased amounts of collagen I and III within the mesangium, glomerular capillary loops, and interstitium, while the amount of collagen IV was normal. Similarly, Northern analysis showed increased expression of mRNA encoding collagen I and III, as well as biglycan and decorin, while the expression of collagen IV was unchanged. These changes began as early as 1 wk of age, a time before the appearance of glomerulosclerosis. 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 evaluated. 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 kidney, local expression of TGF-β1, β2, and β3 protein was similar to wild-type mice. In 5-wk-old transgenic mice, TGF-β1 and β2 protein was present in increased amounts within glomeruli, and renal TGF-β1 mRNA was increased threefold. It is concluded that elevated levels of circulating TGF-β1 may act on the kidney to increase matrix protein production and decrease matrix remodeling. Only after glomerulosclerosis is established does local glomerular overproduction of TGF-β become manifest.

Original languageEnglish
Pages (from-to)271-280
Number of pages10
JournalJournal of the American Society of Nephrology : JASN
Volume10
Issue number2
StatePublished - Feb 1999
Externally publishedYes

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