Rosuvastatin Preserves Renal Structure following Unilateral Ureteric Obstruction in the Neonatal Rat
Rosuvastatin Preserves Renal Structure following Unilateral Ureteric Obstruction in the Neonatal Rat
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DOI：
10.1159/000334935
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发表时间：
2012-01-01
影响因子：
4.2
通讯作者：
Manucha, Walter
中科院分区：
文献类型：
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作者：
Jorgelina Mazzei, Luciana;Mercedes Garcia, Isabel;Manucha, Walter
背景/目的：新生鼠单侧输尿管梗阻(UUO)可作为研究人类宫内梗阻的范例，也可作为研究先天性梗阻性肾病新疗法的平台。本研究探讨了瑞舒伐他汀(ROS)对新生大鼠UUO后肾脏损伤的关键形态计量学指标及相关基因表达的影响。方法：UUO新生大鼠和对照组每天分别给予赋形剂和ROS治疗14天。对肾小管扩张、肾小球大小和数量以及肾小管间质纤维化面积进行量化，并参考适当的肾脏基因表达相关因素来验证变化。结果：UUO使肾小管直径和间质纤维化分别增加2.7倍和7倍，同时增加了肾脏转化生长因子-β(1)和肿瘤坏死因子-α(TNF-α)的mRNA水平。肾小球数量和大小分别减少52%和33%。随着BMP-7和E-钙粘素基因表达水平的降低，梗阻后WT-1mRNA和蛋白的表达减少。ROS可减轻肾小管扩张(33%)和间质纤维化(72%)，并与肾组织转化生长因子-β1和肿瘤坏死因子-α的mRNA水平正常化有关。ROS改善了肾小球的数量和大小(30%和50%)，并保留了WT-1的mRNA和蛋白表达水平以及BMP-7和E-钙粘素的正常mRNA水平。结论：ROS治疗减轻了所有改变，最显著的是间质纤维化的增加。值得注意的是，ROS治疗不能完全挽救肾小球发育。总之，这些数据突出了ROS在新生儿梗阻中的治疗潜力和局限性。版权所有(C)2011 S.Karger AG，巴塞尔
Background/Aims: Unilateral ureteric obstruction (UUO) in neonatal rodents can be used as a paradigm for in utero obstruction in humans and a platform for studying the potential of novel therapies for congenital obstructive nephropathy. The present study examined the effect of rosuvastatin (Ros) on key morphometric measures of renal injury and corresponding gene expression correlates following neonatal UUO in the rat. Methods: Neonatal rats subjected to UUO and controls were treated daily with vehicle or Ros for 14 days. Quantification of tubular dilatation, glomerular size and number and tubulointerstitial fibrotic area was performed and changes validated by reference to appropriate renal gene expression correlates. Results:UUO increased tubular diameter and interstitial fibrosis by 2.7- and 7-fold, respectively, in parallel with increases in renal transforming growth factor-beta(1) (TGF-beta(1)) and tumor necrosis factor-alpha (TNF-alpha) mRNA levels. Glomerular number and size were reduced by 52 and 33%, respectively. Reductions in WT-1 mRNA and protein expression were noted following obstruction occurring in tandem with reduced mRNA levels for BMP-7 and E-cadherin. Ros attenuated tubular dilatation (33%) and interstitial fibrosis (72%) in association with the normalization of renal TGF-beta 1 and TNF-alpha mRNA levels. Ros improved glomerular number and size (30 and 50%), and preserved mRNA and protein expression levels of WT-1 and normalized mRNA levels for BMP-7 and E-cadherin. Conclusions: Ros treatment attenuated all changes, most notably the increase in interstitial fibrosis. Notably, Ros treatment was unable to completely salvage glomerular development. Together these data highlight the therapeutic potential and limitations of Ros in neonatal obstruction. Copyright (C) 2011 S. Karger AG, Basel