Mozes M M, Böttinger E P, Jacot T A, Kopp J B
Institute of Pathophysiology, Semmelweis University Medical School, Budapest, Hungary.
J Am Soc Nephrol. 1999 Feb;10(2):271-80. doi: 10.1681/ASN.V102271.
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.
先前已描述过携带与全长猪转化生长因子-β1（TGF-β1）基因相连的鼠白蛋白增强子/启动子的转基因小鼠的肾脏病理学情况。在这些小鼠中，转基因表达仅限于肝脏，且TGF-β的血浆水平升高。最早的肾脏病理变化是在3周龄时出现肾小球硬化，随后是肾小管间质纤维化。在本研究中，研究者推测循环中的TGF-β1会增加肾脏细胞外基质的积累并激活局部TGF-β基因表达。5周龄时的免疫染色显示，系膜、肾小球毛细血管袢和间质内的I型和III型胶原量增加，而IV型胶原量正常。同样，Northern分析显示，编码I型和III型胶原以及双糖链蛋白聚糖和核心蛋白聚糖的mRNA表达增加，而IV型胶原的表达未改变。这些变化早在1周龄时就开始了，这是在肾小球硬化出现之前的时期。为了评估基质降解情况，通过明胶酶谱法评估了胶原酶IV活性，发现基质金属蛋白酶-2增加。最后，评估了金属蛋白酶组织抑制剂的产生。金属蛋白酶组织抑制剂-1（TIMP-1）mRNA增加了18倍，而TIMP-2和TIMP-3未改变。在2周龄的转基因肾脏中，TGF-β1、β2和β3蛋白的局部表达与野生型小鼠相似。在5周龄的转基因小鼠中，肾小球内TGF-β1和β2蛋白的含量增加，肾脏TGF-β1 mRNA增加了三倍。得出的结论是，循环中TGF-β1水平升高可能作用于肾脏，增加基质蛋白的产生并减少基质重塑。只有在肾小球硬化形成后，局部肾小球TGF-β的过度产生才会显现出来。
