Selective Stabilization of HIF-1α in Renal Tubular Cells by 2-Oxoglutarate Analogues
Selective Stabilization of HIF-1α in Renal Tubular Cells by 2-Oxoglutarate Analogues
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DOI：
10.1016/j.ajpath.2012.07.010
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发表时间：
2012-11-01
影响因子：
6
通讯作者：
Wiliam, Carsten
中科院分区：
文献类型：
--
作者：
Schley, Gunnar;Klanke, Bernd;Wiliam, Carsten
近端肾小管损伤与远端肾小管损伤在急性肾损伤（AM）发病机制中的作用是有争议的。抑制调节缺氧诱导转录因子（hfs）降解的脯氨酰羟化酶是一种很有前途的治疗方法，可以优化缺氧下的能量保存，并已成功应用于AKI模型中保护肾脏结构和功能。目前使用的脯氨酸羟化酶抑制剂是亲脂性的2-氧戊二酸类似物（2OGAs），广泛存在于大多数器官的细胞中。考虑到有机阴离子转运蛋白（OATs）在肾近端小管细胞中的选择性表达，我们假设亲水性2OGAs可以特异性靶向近端小管细胞。我们发现细胞亲水性2OGAs摄取依赖于燕麦，且主要局限于肾脏，仅在近端小管细胞中导致HIF靶基因的激活。在缺血-再灌注实验中，全身活性的2OGA保存了肾脏的结构和功能，但oat1转运的2OGA没有保护作用，这表明HIT稳定在远端小管细胞而不是近端小管细胞和/或非小管细胞中介导保护作用。本研究为基于特异性转运体的近端小管细胞选择性靶向药物的概念提供了证据，揭示了不同肾单元段在AKI病理生理中的作用，并可能为近端小管的长期HIF稳定提供选择，而不会干扰小管周围细胞的促红细胞生成素诱导和不必要的外肾效应。（中华病理学杂志，2012,181:1595-160 http://dx.doi.org/10.1016/j.ajpath.2012.07.010）
The role of proximal versus distal tubular injury in the pathogenesis of acute kidney injury (AM) is debatable. Inhibition of prolyl hydroxylases that regulate the degradation of hypoxia-inducible transcription factors (HIFs) is a promising therapeutic approach to optimize energy preservation under hypoxia and has successfully been applied to protect kidney structure and function in AKI models. Presently used prolyl hydroxylase inhibitors are lipophilic 2-oxoglutarate analogues (2OGAs) that are widely taken up in cells of most organs. Given the selective expression of organic anion transporters (OATs) in renal proximal tubular cells, we hypothesized that hydrophilic 2OGAs can specifically target proximal tubular cells. We found that cellular hydrophilic 2OGAs uptake depended on OATs and largely confined to the kidney, where it resulted in activation of HIF target genes only in proximal tubular cells. When applied in ischemia-reperfusion experiments, systemically active 2OGA preserved kidney structure and function, but OAT1-transported 2OGA was not protective, suggesting that HIT stabilization in distal tubular rather than proximal tubular cells and/or nontubular cells mediates protective effects. This study provides proof of concept for selective drug targeting of proximal tubular cells on the basis of specific transporters, gives insights into the role of different nephron segments in AKI pathophysiology, and may offer options for long-term HIF stabilization in proximal tubules without confounding effects of erythropoietin induction in peritubular cells and unwarranted extrarenal effects. (Am J Pathol 2012, 181:1595-160 http://dx.doi.org/10.1016/j.ajpath.2012.07.010)