Spironolactone prevents chronic kidney disease caused by ischemic acute kidney injury
Spironolactone prevents chronic kidney disease caused by ischemic acute kidney injury
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DOI：
10.1038/ki.2012.352
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发表时间：
2013-01-01
影响因子：
19.6
通讯作者：
Bobadilla, Norma A.
中科院分区：
文献类型：
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作者：
Barrera-Chimal, Jonatan;Perez-Villalva, Rosalba;Bobadilla, Norma A.
急性肾损伤（AKI）已被认为是慢性肾脏疾病（CKD）发展的一个危险因素。醛固酮在促进缺血肾损伤中起关键作用。在这里，我们评估了在缺血引起的AKI之前或之后使用螺内酯是否可以预防CKD。在第一组实验中，Wistar大鼠在没有或事先给予螺内酯治疗的情况下进行假手术，或在缺血前没有或事先给予螺内酯治疗的情况下进行45分钟的双侧肾缺血，并在270天内进行评估。第二组大鼠在假手术或双侧肾缺血后3次给予低剂量（20 mg/kg）或高剂量（80 mg/kg）螺内酯，90天后进行评估。未经治疗的动物在缺血引起的AKI后发展为CKD，其特征是蛋白尿、肾功能障碍、足细胞损伤、肾小球肥大和局灶性硬化的进行性增加。这与氧化应激增加、肿瘤生长因子(TGF)- β的上调以及TGF- β下游效应物phospho-Smad3、胶原I、纤维连接蛋白和促炎细胞因子的上调有关。在缺血之前或之后使用螺内酯治疗通过避免纤维化和炎症途径的激活来预防随后的CKD。因此，螺内酯可能是预防aki诱导的CKD的一种有希望的治疗方法。国际肾脏杂志（2012）83,93 -103；doi: 10.1038 / ki.2012.352;2012年9月26日在线发布
Acute kidney injury (AKI) has been recognized as a risk factor for the development of chronic kidney disease (CKD). Aldosterone has a critical role in promoting renal injury induced by ischemia. Here, we evaluated whether spironolactone administered before or after AKI caused by ischemia protects against CKD. In the first set of experiments, Wistar rats underwent a sham operation without or with prior spironolactone treatment, or underwent 45 minutes of bilateral renal ischemia without or with spironolactone treatment before ischemia and assessed over 270 days. The second set of rats received low (20 mg/kg) or high (80 mg/kg) doses of spironolactone at three different times after the sham operation or bilateral renal ischemia and were assessed after 90 days. Untreated animals developed CKD following ischemia-induced AKI as characterized by a progressive increase in proteinuria, renal dysfunction, podocyte injury, glomerular hypertrophy, and focal sclerosis. This was associated with increased oxidative stress, an upregulation of tumor growth factor (TGF)-beta, followed by upregulation of the TGF-beta downstream effectors phospho-Smad3, collagen I, fibronectin, and proinflammatory cytokines. Treatment with spironolactone either before or after ischemia prevented subsequent CKD by avoiding the activation of fibrotic and inflammatory pathways. Thus, spironolactone may be a promising treatment for the prevention of AKI-induced CKD. Kidney International (2012) 83, 93-103; doi:10.1038/ki.2012.352; published online 26 September 2012