Perturbed medullary tubulogenesis in neonatal rat exposed to renin-angiotensin system inhibition
Perturbed medullary tubulogenesis in neonatal rat exposed to renin-angiotensin system inhibition
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DOI：
10.1093/ndt/gfg447
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发表时间：
2003-12-01
影响因子：
6.1
通讯作者：
Friberg, P
中科院分区：
文献类型：
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作者：
Lasaitiene, D;Chen, Y;Friberg, P
背景在大鼠肾发生过程中，血管紧张素II 1型受体（AT（1））信号传导的药理学中断可诱导不可逆的肾脏形态异常，包括乳头状萎缩和肾小管间质损伤，其特征为肾小管扩张/萎缩和间质炎症/纤维化。本研究确定了暴露于血管紧张素转换酶（ACE）抑制剂的新生大鼠肾髓质中肾小管结构和炎症变化以及可能的细胞因子产生的时间过程。此外，在ACE抑制大鼠中研究了髓质中E-钙粘蛋白（肾小管形成的标志物）的表达。新生大鼠暴露（出生后第0-12天）ACE抑制剂依那普利，并在第1，2，4，9和13天处死。一个肾脏用于形态学评价，另一个用于免疫组织化学，使用针对冷冻切片上的单核细胞/巨噬细胞、T细胞和E-钙粘蛋白的抗体。在另一项实验中，大鼠接受9天的治疗，并对其肾脏进行Western免疫印迹和免疫组织化学处理，其中针对单核细胞趋化蛋白-1（MCP-1）和肿瘤坏死因子-α（TNF-α）的抗体用于石蜡切片。在肾髓质依那普利治疗的大鼠，管腔和肾小管的体积分数分别从出生后第2天和第4天增加，而肾小管细胞的体积分数从第4天开始下降。在依那普利给药大鼠扩张的髓质小管中观察到E-钙粘蛋白表达的伴随损失和/或减少（从第2天开始）。此外，在依那普利处理大鼠的髓质中，分别在第9天和第13天观察到ED 2+（驻留巨噬细胞）细胞数量增加，随后ED 1+（单核细胞/巨噬细胞）和CD 4 + T细胞增加。这伴随着在第9天髓表达TNF-α的增加。新生儿ACE抑制扰乱髓质小管发生，如肾小管扩张和缺乏E-钙粘蛋白表达在这些小管。巨噬细胞/单核细胞介导的免疫应答是继发性事件，巧合地与TNF-α的上调相关。
Background. Pharmacological interruption of the angiotensin II type-1 receptor (AT(1)) signalling during nephrogenesis in rats induces irreversible abnormalities in kidney morphology, comprising papillary atrophy and tubulointerstitial damage, which are characterized by tubular dilatation/atrophy and interstitial inflammation/fibrosis. This study determined the time course for development of tubular structural and inflammatory changes and possible cytokine production in the renal medulla of newborn rats exposed to angiotensin-converting enzyme (ACE) inhibition. Additionally, medullary expression of E-cadherin, a marker for tubular formation, was investigated in ACE-inhibited rats.Methods. Newborn rats were exposed (postnatal days 0-12) to ACE inhibitor enalapril and killed at days 1, 2, 4, 9 and 13. One kidney was used for morphological evaluation and the other for immunohistochemistry, using antibodies directed against monocytes/ macrophages, T cells and E-cadherin on frozen sections. In a separate experiment, rats were treated for 9 days and had their kidneys processed for western immuno-blot and immunohistochemistry, where antibodies directed against monocyte chemoattractant protein-1 (MCP-1) and tumour necrosis factor-alpha (TNF-alpha) were used on paraffin sections.Results. In renal medulla from enalapril-treated rats, volume fractions of tubular lumens and interstitium were increased from postnatal days 2 and 4, respectively, while that of tubular cells was decreased from 4 days of age. Concomitant loss and/or reduction in E-cadherin expression (from day 2) was observed in dilated medullary tubules of enalapril-treated rats. Furthermore, in the medulla of enalapril-treated rats, the increased number of ED2+ (resident macrophages) cells, followed by the increase in ED1+ (monocytes/ macrophages) and CD4+ T cells, was observed at days 9 and 13, respectively. This was accompanied by increased medullary expression of TNF-alpha at day 9.Conclusions. Neonatal ACE inhibition perturbs medullary tubulogenesis, as indicated by tubular dilatation and a lack of E-cadherin expression in these tubules. Macrophage/monocyte-mediated immune response is a secondary event, coincidentally associated with the up-regulation of TNF-alpha.