Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure
Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure
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DOI：
10.1681/asn.2005121302
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发表时间：
2006-07-01
影响因子：
13.6
通讯作者：
Eckardt, Kai-Uwe
中科院分区：
文献类型：
--
作者：
Bernhardt, Wanja M.;Campean, Valentina;Eckardt, Kai-Uwe
低氧诱导转录因子（HIT）的激活是细胞适应低氧环境的重要机制。HIF的常氧降解是通过HIT脯氨酰羟化酶（PHD）对调节性α-亚基的特定脯氨酰残基的氧依赖性羟基化介导的。假设通过缺氧或PHD的药理学抑制来抑制HIF降解将赋予针对随后的缺血性损伤的保护。为了验证这一假设，在大鼠中通过在右侧肾切除术后夹闭左肾动脉40分钟来诱导缺血性急性肾衰竭。在手术前，使用一氧化碳预处理，导致组织缺氧，或使用新型PHD抑制剂FG-4487。未观察到FG-4487的毒性作用。两种预处理均强烈诱导HIF-1 α和HIF-2 α分别在肾小管和管周细胞中积累，以及HIF靶基因表达。两种预处理策略均显著改善了随后的缺血性损伤过程，24和72 h后血清肌酐和血清尿素的显著改善证明了这一点。此外，组织损伤和细胞凋亡的严重程度较低，这是量化的应用标准化组织学评分系统在一个盲的方式。总之，这些数据提供了HIF系统的预条件激活防止缺血性损伤的原理证据。因此，抑制HIF羟化酶的活性似乎具有相当大的临床前景。
Activation of hypoxia-inducible transcription factor (HIT) has been identified as an important mechanism of cellular adaptation to low oxygen. Normoxic degradation of HIF is mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative alpha-subunits by HIT prolyl hydroxylases (PHD). It was hypothesized that inhibition of HIF degradation by either hypoxia or pharmacologic inhibition of PHD would confer protection against subsequent ischemic injury. For testing this hypothesis ischernic acute renal failure was induced in rats by 40 min of clamping of the left renal artery after right-sided nephrectomy. Before surgery, pretreatment with either carbon monoxide, leading to tissue hypoxia, or the novel PHD inhibitor FG-4487 was applied. No toxic effects of FG-4487 were observed. Both pretreatments strongly induced the accumulation of HIF-1 alpha and HIF-2 alpha in tubular and peritubular cells, respectively, as well as HIF target gene expression. The course of subsequent ischernic injury was significantly ameliorated by both strategies of preconditioning, as evident from a significant improvement of serum creatinine and serum urea after 24 and 72 h. Furthermore, tissue injury and apoptosis were less severe, which were quantified by application of a standardized histologic scoring system in a blinded manner. In conclusion, the data provide proof of principle that preconditional activation of the HIF system protects against ischernic injury. Inhibiting the activity of HIF hydroxylases therefore seems to have considerable clinical perspectives.