Yang C W, Striker G E, Chen W Y, Kopchick J J, Striker L J
Renal Cell Biology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1268, USA.
Lab Invest. 1997 Apr;76(4):467-76.
We found that mice transgenic for native bovine growth hormone (bGH) gene had increased body size and rapidly progressive glomerulosclerosis, whereas mice transgenic for a mutated bGH gene (bGH-m11) had near normal body size and slowly progressive glomerulosclerosis. The aim of this study was to determine whether rapidly and slowly progressive glomerulosclerosis had distinct glomerular extracellular matrix (ECM) and growth factor mRNA levels. ECM and growth factors were quantitated by competitive reverse transcriptase-PCR in microdissected glomeruli from bGH, bGH-m11, and nontransgenic littermate control mice. In rapid progressors (bGH mice) at 2 to 3 months, the levels of mRNA-coding for some glomerular ECM and growth factors were increased (alpha 1(IV) collagen, 7.3-fold; laminin B1, 3.9-fold; tenascin, 8-fold; and tumor growth factor (TGF)-beta 1, 3.4-fold). These levels underwent a further 2.3-fold increase at 6 to 9 months. Platelet-derived growth factor (PDGF)-B mRNA was high at 2 to 3 months (7.4-fold) and 6 to 9 months (9.5-fold) and was associated with an increased [3H]-thymidine-labeling index and glomerular cell number. In slow progressors (bGH-m11 mice), the mRNA levels at 2 to 3 months were approximately one half that of rapid progressors (alpha 1(IV) collagen, 3.4-fold; laminin B1 1.9-fold; tenascin, 3-fold; TGF-beta 1, 2.2-fold). PDGF-B levels were normal. At 6 to 9 months, alpha 1(IV) collagen, TGF-beta 1, and PDGF-B mRNA levels doubled, whereas tenascin and laminin B1 levels remained stable. At 12 to 18 months, the alpha 1(IV) collagen, TGF-beta 1, and tenascin levels increased by nearly another 50%. The labeling index and PDGF levels were not increased at any time. The levels of expression of several glomerular ECM mRNA and growth factors of rapid progressors at 2 to 3 months of age was nearly double that of slow progressors, nearly doubling again by 6 to 9 months. In slow progressors, alpha 1(IV) collagen and TGF-beta 1 mRNA levels continued to increase at a slow rate, but tenascin and laminin mRNA levels were only further increased at 12 to 18 months. Thus, the initial levels of these mRNA and their rate of change correlated with the severity of glomerulosclerosis.
我们发现，转天然牛生长激素（bGH）基因的小鼠体型增大，且出现快速进展性肾小球硬化，而转突变bGH基因（bGH-m11）的小鼠体型接近正常，且肾小球硬化进展缓慢。本研究的目的是确定快速进展性和缓慢进展性肾小球硬化是否具有不同的肾小球细胞外基质（ECM）和生长因子mRNA水平。通过竞争性逆转录-聚合酶链反应（PCR）对来自bGH、bGH-m11和非转基因同窝对照小鼠的显微切割肾小球中的ECM和生长因子进行定量分析。在2至3个月大的快速进展者（bGH小鼠）中，一些肾小球ECM和生长因子的mRNA编码水平升高（α1（IV）胶原，7.3倍；层粘连蛋白B1，3.9倍；腱生蛋白，8倍；肿瘤生长因子（TGF）-β1，3.4倍）。这些水平在6至9个月时进一步升高2.3倍。血小板衍生生长因子（PDGF）-B mRNA在2至3个月（7.4倍）和6至9个月（9.5倍）时较高，且与[3H]-胸腺嘧啶核苷标记指数和肾小球细胞数量增加相关。在缓慢进展者（bGH-m11小鼠）中，2至3个月时的mRNA水平约为快速进展者的一半（α1（IV）胶原，3.4倍；层粘连蛋白B1，1.9倍；腱生蛋白，3倍；TGF-β1，2.2倍）。PDGF-B水平正常。在6至9个月时α1（IV）胶原、TGF-β1和PDGF-B mRNA水平翻倍，而腱生蛋白和层粘连蛋白B1水平保持稳定。在12至18个月时，α1（IV）胶原、TGF-β1和腱生蛋白水平又增加了近50%。标记指数和PDGF水平在任何时候都没有增加。2至3个月大的快速进展者中几种肾小球ECM mRNA和生长因子的表达水平几乎是缓慢进展者的两倍，在6至9个月时又几乎翻倍。在缓慢进展者中，α1（IV）胶原和TGF-β1 mRNA水平继续缓慢升高，但腱生蛋白和层粘连蛋白mRNA水平仅在12至18个月时进一步升高。因此，这些mRNA的初始水平及其变化率与肾小球硬化的严重程度相关。
