Transient myofibroblast differentiation of interstitial fibroblastic cells relevant to tubular dilatation in uranyl acetate-induced acute renal failure in rats
Transient myofibroblast differentiation of interstitial fibroblastic cells relevant to tubular dilatation in uranyl acetate-induced acute renal failure in rats
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DOI：
10.1007/s00428-004-1155-5
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发表时间：
2005-02-01
期刊：
影响因子：
3.5
通讯作者：
Hishida, A
中科院分区：
文献类型：
--
作者：
Fujigaki, Y;Muranaka, Y;Hishida, A
为探讨醋酸铀酰诱导的急性肾功能衰竭(ARF)大鼠肾间质成纤维细胞(FCS)向肌成纤维细胞分化的机制，观察了α-SMA的表达、肌成纤维细胞表型与肾小管扩张、FCS细胞形态及黏附的关系。肾小管周围α-SMA阳性的肌成纤维细胞在ARF诱导后出现，并沿受损、扩张的近端小管延伸，近端肾小管恢复后几乎消失。近端小管周长与α-SMA染色的分数面积相关(P<；0.001)。大多数α-SMA阳性细胞不掺入[H-3]-胸腺嘧啶核苷，表明增殖活性较低。透射电子显微镜显示，肾小管上皮细胞以细长的含有细胞质的微丝束附着于肾小管基底膜，从第4天到第7天形成大量的黏附和缝隙连接。扫描电子显微镜显示，在ARF诱导后，大量肥大的FCS覆盖在肾小管上。在ARF后给予抑制细胞骨架运动的氯丙嗪，在免疫组织化学和形态学上部分抑制了FCS的肌成纤维细胞分化，并在第4天时导致近端小管扩张，肾功能障碍加重，再生修复受到抑制。我们的结果表明，在醋酸铀酰诱导的ARF大鼠中，机械张力可能通过调节张力稳态而导致α-SMA表型的诱导，增加了FCS中应力纤维的形成和细胞间连接，以支持受损的肾单位结构。
To investigate the mechanisms of myofibroblast differentiation of interstitial fibroblastic cells (FCs) in rats with uranyl acetate-induced acute renal failure (ARF), we examined the relationship between the expression of alpha-smooth muscle actin (alpha-SMA), myofibroblast phenotype and tubular dilatation as well as cell shape and adhesion of FCs. Peritubular alpha-SMA-positive myofibroblasts appeared after induction of ARF and extended along the damaged, dilated proximal tubules and then almost disappeared after proximal tubular recovery. The perimeter of proximal tubules correlated with fractional areas stained for alpha-SMA (P< 0.001). Most alpha-SMA-positive cells did not incorporate [H-3]-thymidine, indicating a low proliferative activity. Transmission electron microscopy showed that FCs increasingly attached to the tubular basement membrane by elongated cytoplasm-containing microfilament bundles, which formed abundant adherens and gap junctions from day 4 to day 7. Scanning electron microscopy showed hypertrophic FCs covering large areas of tubules after induction of ARF. Administration of chlorpromazine, which can inhibit cytoskeletal movement, after induction of ARF partially inhibited myofibroblast differentiation of FCs immunohistochemically and morphologically and resulted in more dilated proximal tubules in concert with aggravation of renal dysfunction and inhibition of regenerative repair at day 4 than vehicle-administered rats. Our results indicate that mechanical tension, judged by tubular dilatation, may contribute to the induction of alpha-SMA phenotype with increased stress fiber formation and intercellular junctions in FCs to support damaged nephron structures by adjusting tensional homeostasis in rats with uranyl acetate-induced ARF.