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-beta1 (TGF-beta1) gene has been described previously. In these mice, transgene expression is limited to the liver and the plasma level of TGF-beta 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-beta1 increases renal extracellular matrix accumulation and activates local TGF-beta 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-beta1, beta2, and beta3 protein was similar to wild-type mice. In 5-wk-old transgenic mice, TGF-beta1 and beta2 protein was present in increased amounts within glomeruli, and renal TGF-beta1 mRNA was increased threefold. It is concluded that elevated levels of circulating TGF-beta1 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-beta become manifest.
Mozes
M M
MM
Institute of Pathophysiology, Semmelweis University Medical School, Budapest, Hungary.
Böttinger
E P
EP
Jacot
T A
TA
Kopp
J B
JB
D000818:Animals; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D007536:Isomerism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic / Q000033:anatomy & histology / Q000235:genetics* / Q000378:metabolism*; D011509:Proteoglycans / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism*
D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D003094:Collagen; D008666:Metalloendopeptidases