Minto A W, Kalluri R, Togawa M, Bergijk E C, Killen P D, Salant D J
Evans Memorial Department of Clinical Research, Boston University Medical Center, MA 02118, USA.
Proc Assoc Am Physicians. 1998 May-Jun;110(3):207-17.
In human and experimental membranous nephropathy, new extracellular matrix accumulates between, and eventually surrounds, immune deposits on the subepithelial aspect of the glomerular basement membrane (GBM). To define the nature and source of this newly deposited matrix, we studied by in situ hybridization and immunohistology the production and tissue deposition of the recently defined basement membrane type IV collagen chain isoforms alpha3, alpha4, and alpha5, the mesangium-specific alpha1 and alpha2 isoforms of type IV collagen, and the fibrillar interstitial type I collagen during the development of immunological injury in passive Heymann nephritis (PHN), a rodent model of membranous nephropathy. Our results show that steady-state mRNA levels of alpha3-alpha5 (IV) but not alpha1 (IV) are significantly increased in the glomeruli of rats with PHN at the peak of immunological injury after 14 days. Increased signal for alpha4 (IV) and the new appearance of alpha1 (I) could be clearly localized to glomerular podocytes, the target of injury in this model. In addition, increased levels of immunoreactive alpha3-alpha5 were visible in the peripheral and paramesangial GBM together with de novo deposits of type I collagen. A modest increase in mesangial staining for alpha1/alpha2 (IV) was present in PHN glomeruli. In rats depleted of complement for 5 days after PHN induction, the peak of alpha4 (IV) mRNA expression on day 14 was blunted. In conclusion, we have shown increased production of the intrinsic GBM type IV collagen isoforms alpha3-alpha5 and ectopic production of type I collagen by injured podocytes in PHN. These changes may contribute to the formation of an expanded and disorganized GBM, as seen in experimental and human membranous nephropathy.
在人类和实验性膜性肾病中，新的细胞外基质在肾小球基底膜（GBM）上皮下侧的免疫沉积物之间积聚，并最终将其包围。为了确定这种新沉积基质的性质和来源，我们通过原位杂交和免疫组织学方法，研究了最近确定的基底膜IV型胶原链异构体α3、α4和α5、IV型胶原的系膜特异性α1和α2异构体以及纤维状间质I型胶原在被动型Heymann肾炎（PHN，一种膜性肾病的啮齿动物模型）免疫损伤发展过程中的产生和组织沉积情况。我们的结果表明，在免疫损伤高峰期（14天后），PHN大鼠肾小球中α3 - α5（IV）而非α1（IV）的稳态mRNA水平显著升高。α4（IV）信号增强以及α1（I）的新出现可明确定位于肾小球足细胞，该模型中的损伤靶点。此外，在周边和系膜旁GBM中可见免疫反应性α3 - α5水平升高，同时伴有I型胶原的新生沉积。PHN肾小球中系膜α1/α2（IV）染色有适度增加。在PHN诱导后5天补体耗竭的大鼠中，第14天α4（IV）mRNA表达的峰值减弱。总之，我们已经表明，在PHN中，损伤的足细胞增加了内源性GBM IV型胶原异构体α3 - α5的产生，并异位产生了I型胶原。这些变化可能有助于形成如在实验性和人类膜性肾病中所见的扩展且紊乱的GBM。
