Zhang G, Moorhead P J, el Nahas A M
Scheffield Kidney Institute, Northern General Hospital, Sheffield, UK.
Exp Nephrol. 1995 Sep-Oct;3(5):308-18.
We have studied the sequential morphological changes that took place in the kidneys of 8 rats with nephrotoxic serum nephritis (NTN). Rats underwent kidney biopsies at different time intervals (days 7, 15, 30, 90 and 120). The tissues were processed for light microscopy as well as immunohistochemistry for inflammatory cellular infiltrate as well as for the components of the extracellular matrix (ECM) and myofibroblasts (cells expressing alpha-smooth muscle actin, alpha-SMA). Nephrotic rats developed severe proteinuria, impaired renal function as well as progressive renal scarring. However, the natural history of NTN was heterogeneous with some rats recovering (n = 5) and other progressing to end-stage renal failure (n = 3). The heterogeneous nature of the glomerulonephritis has established that those with a good outcome had a stabilisation, with some resolution, of the deposited ECM and of the scarring process. By contrast, rats with a poor outcome had a progressive increase in glomerular as well as interstitial ECM. Cells expressing alpha-SMA (myofibroblasts) were detected in the glomeruli as well as in the interstitium of nephritic rats. Changes in the expression of cells expressing alpha-SMA paralleled those of the components of the ECM in particular fibronectin. alpha-SMA immunostain was the best predictor of progression. Early glomerular alpha-SMA immunostain (days 7 and 30) was a strong predictor of the subsequent development of glomerulosclerosis and renal dysfunction. The predictive value of interstitial alpha-SMA immunostain on days 7 for subsequent tubulo-interstitial scarring and renal insufficiency was also strong and exceeded that of other histological or immunohistochemical parameters of scarring. This study establishes the natural history of experimental renal scarring and identifies a renal cell type, the myofibroblast, as a useful marker of progression. It also suggests a role for myofibroblasts in the progression of glomerulosclerosis and tubulo-interstitial fibrosis.
我们研究了8只患有肾毒性血清性肾炎（NTN）大鼠肾脏中发生的一系列形态学变化。大鼠在不同时间间隔（第7天、15天、30天、90天和120天）接受肾脏活检。组织进行了光镜检查以及免疫组化，以检测炎性细胞浸润、细胞外基质（ECM）成分和肌成纤维细胞（表达α-平滑肌肌动蛋白，α-SMA的细胞）。肾病大鼠出现严重蛋白尿、肾功能受损以及进行性肾瘢痕形成。然而，NTN的自然病程具有异质性，一些大鼠恢复（n = 5），另一些则进展为终末期肾衰竭（n = 3）。肾小球肾炎的异质性表明，预后良好的大鼠其沉积的ECM和瘢痕形成过程有一定程度的稳定并有所消退。相比之下，预后不良的大鼠肾小球和间质ECM则进行性增加。在肾炎大鼠的肾小球和间质中均检测到表达α-SMA的细胞（肌成纤维细胞）。表达α-SMA的细胞的变化与ECM成分尤其是纤连蛋白的变化平行。α-SMA免疫染色是疾病进展的最佳预测指标。早期肾小球α-SMA免疫染色（第7天和30天）是随后发生肾小球硬化和肾功能障碍的有力预测指标。第7天间质α-SMA免疫染色对随后肾小管间质瘢痕形成和肾功能不全的预测价值也很强，且超过了其他瘢痕形成的组织学或免疫组化参数。本研究确定了实验性肾瘢痕形成的自然病程，并确定了一种肾细胞类型，即肌成纤维细胞，作为疾病进展的有用标志物。它还提示了肌成纤维细胞在肾小球硬化和肾小管间质纤维化进展中的作用。
