Genomic-Derived Markers for Early Detection of Calcineurin Inhibitor Immunosuppressant-Mediated Nephrotoxicity
Genomic-Derived Markers for Early Detection of Calcineurin Inhibitor Immunosuppressant-Mediated Nephrotoxicity
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DOI：
10.1093/toxsci/kfr217
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发表时间：
2011-11-01
影响因子：
3.8
通讯作者：
Paules, Richard S.
中科院分区：
文献类型：
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作者：
Cui, Yuxia;Huang, Qihong;Paules, Richard S.
钙调神经磷酸酶抑制剂（CI）治疗与慢性肾毒性有关，这限制了其抑制同种异体移植排斥的长期用途。为了了解毒性机制，我们分析了雄性 Sprague-Dawley 大鼠每日服用环孢素（CsA；2.5 或 25 mg/kg/天）、FK506（0.6 或 6 mg/kg/天）或雷帕霉素（1 或 10 mg/kg/天）1、7 次后，CI 免疫抑制剂介导的肾毒性发生的基因表达变化。 14 或 28 天。在用 CsA（高）或 FK506（高）治疗 14 和 28 天的动物中观察到血液尿素氮显着增加。组织病理学检查显示给予 CsA（高）或 FK506（低和高）的动物存在肾小管嗜碱性粒细胞增多和矿化。我们鉴定了一组在大鼠肾脏中表达与 CI 诱导的肾损伤相关的基因。这些基因中有两个基因：Slc12a3 和肾脏特异性 Wnk1 (KS-Wnk1)，已知它们参与远端肾单位的钠转运，并可能参与 CI 诱导的肾毒性机制。通过免疫组织化学染色证实了 CI 治疗后大鼠肾脏中 NCC（由 Slc12a3 编码的 Na-Cl 协同转运蛋白）的下调，并通过定量实时聚合酶链反应（qRT-PCR）证实了 KS-Wnk1 的下调。我们假设 Slc12a3 和 KS-Wnk1 表达的减少可能会改变远端肾小管的氯化钠重吸收，并有助于延长肾素-血管紧张素系统的激活，这在动物模型和临床环境中都被证明是 CI 诱导肾毒性发生的原因。因此，如果在人体中验证为生物标志物，SLC12A3 和 KS-WNK1 在临床实践中监测肾脏异种移植健康状况时，可能有助于早期检测和减少免疫抑制移植患者的 CI 相关肾毒性。
Calcineurin inhibitor (CI) therapy has been associated with chronic nephrotoxicity, which limits its long-term utility for suppression of allograft rejection. In order to understand the mechanisms of the toxicity, we analyzed gene expression changes that underlie the development of CI immunosuppressant-mediated nephrotoxicity in male Sprague-Dawley rats dosed daily with cyclosporine (CsA; 2.5 or 25 mg/kg/day), FK506 (0.6 or 6 mg/kg/day), or rapamycin (1 or 10 mg/kg/day) for 1, 7, 14, or 28 days. A significant increase in blood urea nitrogen was observed in animals treated with CsA (high) or FK506 (high) for 14 and 28 days. Histopathological examination revealed tubular basophilia and mineralization in animals given CsA (high) or FK506 (low and high). We identified a group of genes whose expression in rat kidney is correlated with CI-induced kidney injury. Among these genes are two genes, Slc12a3 and kidney-specific Wnk1 (KS-Wnk1), that are known to be involved in sodium transport in the distal nephrons and could potentially be involved in the mechanism of CI-induced nephrotoxicity. The downregulation of NCC (the Na-Cl cotransporter coded by Slc12a3) in rat kidney following CI treatment was confirmed by immunohistochemical staining, and the downregulation of KS-Wnk1 was confirmed by quantitative real-time-polymerase chain reaction (qRT-PCR). We hypothesize that decreased expression of Slc12a3 and KS-Wnk1 could alter the sodium chloride reabsorption in the distal tubules and contribute to the prolonged activation of the renin-angiotensin system, a demonstrated contributor to the development of CI-induced nephrotoxicity in both animal models and clinical settings. Therefore, if validated as biomarkers in humans, SLC12A3 and KS-WNK1 could potentially be useful in the early detection and reduction of CI-related nephrotoxicity in immunosuppressed transplant patients when monitoring the health of kidney xenographs in clinical practice.