LONG-TERM TREATMENT OF RATS WITH FGF-2 RESULTS IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS
LONG-TERM TREATMENT OF RATS WITH FGF-2 RESULTS IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS
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DOI：
10.1038/ki.1995.433
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发表时间：
1995-11-01
影响因子：
19.6
通讯作者：
ELGER, H
中科院分区：
文献类型：
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作者：
KRIZ, W;HAHNEL, B;ELGER, H
用FGF-2对大鼠进行长期治疗（8周和13周）导致白蛋白尿和血清肌酐增加，表明慢性肾衰竭的发展。组织学上，发现局灶节段性肾小球硬化（FSGS）的经典图片;男性比女性更严重的影响。在早期变化中，足细胞病变最为突出。令人惊讶的是，在给药动物中发现足细胞有丝分裂像和相当大比例的双（多）核足细胞特征（雄性约16%，雌性约8%）。由于足细胞数量的增加不明显，我们得出结论，FGF-2刺激足细胞重新进入细胞周期并进行有丝分裂（核分裂）。然而，足细胞-可能是由于它们在成年时高度分化的细胞形状-不能完成细胞分裂（胞质分裂），导致双核或多核细胞;在其他情况下，细胞分裂可能完全失败，导致足细胞变性。FGF-2处理的大鼠中的大多数足细胞表现出退行性变化，包括细胞体衰减、广泛的假囊肿形成、广泛的足突消失以及从肾小球基底膜（GEM）脱附。FSGS在该模型中的发展是非常均匀的。在足细胞从外周毛细血管脱离的情况下，壁细胞附着到裸GEM区域，建立了用于发展簇粘附到Bowman囊的病灶。壁细胞侵入相邻的毛细血管袢形成丛状粘连，最终导致毛细血管塌陷，即节段性硬化。Bowman囊内表面的粘连分布似乎是随机的，包括血管和泌尿极之间的所有位置。这项研究的两个主要方面（足细胞无法复制和基于足细胞退化的FSGS发展）可能是恶性循环的一部分。FGF-2刺激足细胞进入细胞分裂，从而将它们带入危险境地。如果足细胞发生故障并退化，则无法替换，从而加剧剩余细胞的情况，并可能增加它们对促有丝分裂刺激做出反应的倾向。类似的机制可能构成FSGS在其他实验以及人类肾小球疾病的发展。
Long-term treatment (8 and 13 weeks) of rats with FGF-2 led to albuminuria and to increase in serum creatinine indicating the development of chronic renal failure. Histologically, the classic picture of focal segmental glomerulosclerosis (FSGS) was found; males were more severely affected than females. Among the early changes podocyte lesions were most prominent. Surprisingly, mitotic figures in podocytes and a considerable fraction of bi(multi)nucleated podocyte profiles were found in treated animals (roughly 16% in males, 8% in females). Since an increase of cell number of podocytes was not evident, we conclude that FGF-2 stimulates podocytes to re-enter the cell cycle and to undergo mitosis (nuclear division). However, podocytes-probably due to their highly differentiated cell shape in the adult-are unable to complete cell division (cytokinesis) resulting in bi- or multinucleated cells; in others cell division may fail totally leading to podocyte degeneration. Most podocytes in FGF-2-treated rats exhibited degenerative changes including cell body attenuation, extensive pseudocyst formation, widespread foot process effacement, as well as detachments from the glomerular basement membrane (GEM). The development of FSGS in this model is very uniform. In the case of podocyte detachments from peripheral capillaries, parietal cells become attached to naked GEM-areas, establishing the nidus for development of a tuft adhesion to Bowman's capsule. Tuft adhesions grow by encroaching of parietal cells onto adjacent capillary loops, resulting eventually in a solid synechia with collapsed capillaries, that is, what represents segmental sclerosis. The distribution of adhesions on the inner surface of Bowman's capsule appeared to be random, including all locations between the vascular and urinary pole. The two main aspects of this study (inability of podocytes to replicate and development of FSGS based on progressing podocyte degeneration) may be part of a vicious cycle. FGF-2 stimulates podocytes to enter cell division thereby conveying them into a hazardous situation. If a podocyte fails and degenerates it cannot be replaced, aggravating the situation for the remaining cells and possibly increasing their predisposition to respond to mitogenic stimuli. Similar mechanisms may constitute the development of FSGS in other experimental as well as human glomerulopathies.