Chertin Boris, Farkas Amicur, Puri Prem
Children's Research Centre, Our Lady's Hospital for Sick Children, University College Dublin, Dublin, Ireland.
Pediatr Surg Int. 2004 Apr;20(4):283-9. doi: 10.1007/s00383-003-1127-x. Epub 2004 Feb 4.
Reflux nephropathy (RN) is recognised as a major cause of end-stage renal failure in children and young adults. Insulin-like growth factor-1 (IGF-1), a peptide growth factor produced by collecting ducts, and its receptor, insulin-like growth factor-1 receptor (IGF-1R), are present in the glomeruli and basolateral membrane of renal proximal tubular cells. Exogenous IGF-1 has been shown to enhance proliferation and reduce apoptosis of tubular cells following renal injury.
We designed this study to investigate the expression of IGF-1 in RN. The kidney specimens from 15 children with RN were obtained at the time of nephrectomy. Control material included normal kidney specimens obtained from adult patients during partial nephrectomy for an incidentaloma. Single-label immunofluorescence histochemistry was carried out using polyclonal antibodies to IGF-1 and IGF-1R employing laser scanning confocal microscopy. Double-label immunofluorescence histochemistry was carried out using monoclonal antibodies to vimentin and clusterin to assess tubulointerstitial fibrosis. IGF-1 and IGF-1R gene expression were evaluated by in situ hybridisation (ISH). The TUNEL method was utilised to assess tubular apoptosis.
In the normal kidney there was strong IGF-1 and IGF-1R immunoreactivity in the proximal tubules, whereas IGF-1 and IGF-1R immunoreactivity was markedly reduced in RN specimens. Strong IGF-1 and IGF-1R mRNA expression was observed in the proximal tubules in normal kidneys, whereas IGF-1 and IGF-1R mRNA expression was undetectable in RN. Renal tubulointerstitial expression of vimentin and clusterin was markedly increased in RN kidneys. Decreased IGF-1 and IGF-1R expression in RN strongly correlated with severity of tubular apoptosis in RN compared with controls.
These data suggest that the downregulation of IGF-1 and IGF-1R may play an important role in the pathogenesis of RN, at least in part by increasing interstitial collagen deposition and tubular apoptosis.
反流性肾病（RN）被认为是儿童和年轻成人终末期肾衰竭的主要原因。胰岛素样生长因子-1（IGF-1）是一种由集合管产生的肽生长因子，其受体胰岛素样生长因子-1受体（IGF-1R）存在于肾小球和肾近端小管细胞的基底外侧膜中。外源性IGF-1已被证明可增强肾损伤后肾小管细胞的增殖并减少其凋亡。
我们设计了这项研究来调查IGF-1在RN中的表达。15例RN患儿的肾脏标本在肾切除时获取。对照材料包括在因偶然发现的肿瘤行部分肾切除术时从成年患者获取的正常肾脏标本。使用针对IGF-1和IGF-1R的多克隆抗体，采用激光扫描共聚焦显微镜进行单标记免疫荧光组织化学。使用针对波形蛋白和聚集素的单克隆抗体进行双标记免疫荧光组织化学，以评估肾小管间质纤维化。通过原位杂交（ISH）评估IGF-1和IGF-1R基因表达。采用TUNEL法评估肾小管凋亡。
在正常肾脏中，近端小管有强烈的IGF-1和IGF-1R免疫反应性，而在RN标本中IGF-1和IGF-1R免疫反应性明显降低。在正常肾脏的近端小管中观察到强烈的IGF-1和IGF-1R mRNA表达，而在RN中未检测到IGF-1和IGF-1R mRNA表达。波形蛋白和聚集素在RN肾脏中的肾小管间质表达明显增加。与对照组相比，RN中IGF-1和IGF-1R表达降低与RN中肾小管凋亡的严重程度密切相关。
这些数据表明，IGF-1和IGF-1R的下调可能在RN的发病机制中起重要作用，至少部分是通过增加间质胶原沉积和肾小管凋亡来实现的。
