Overexpression of cyclooxygenase-2 predisposes to podocyte injury
Overexpression of cyclooxygenase-2 predisposes to podocyte injury
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DOI：
10.1681/asn.2006090990
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发表时间：
2007-02-01
影响因子：
13.6
通讯作者：
Harris, Raymond C.
中科院分区：
文献类型：
--
作者：
Cheng, Huifang;Wang, Suwan;Harris, Raymond C.
在肾脏消融和 Thy-1 肾炎后的大鼠以及培养的小鼠足细胞中，足细胞环氧合酶 2 (COX-2) 表达增加，以响应机械应激。为了研究COX-2过表达是否在足细胞损伤中发挥作用，建立了转基因B6/D2小鼠，其中COX-2表达由去氧肾上腺素启动子驱动。免疫印迹和免疫组织化学证实了转基因小鼠肾脏足细胞中 COX-2 表达的选择性上调。研究了足细胞特异性 COX-2 表达的上调是否增强了对阿霉素肾病发展的敏感性。与野生型同窝小鼠相比，阿霉素给药显着诱导转基因小鼠出现更多的蛋白尿和足突消失，并降低肾小球去氧肾上腺素 mRNA 和免疫反应性。与野生型小鼠相比，阿霉素还显着增加了转基因小鼠足细胞中免疫反应性 COX-2 的表达。逆转录酶-PCR表明，这种增加代表内源性COX-2 mRNA表达的刺激，而不是由去氧肾上腺素启动子驱动的COX-2 mRNA表达。对阿霉素肾损伤敏感的 Balb/C 小鼠也响应药物给药而增加了足细胞 COX-2 的表达并减少了去氧肾上腺素的表达。长期使用 COX-2 特异性抑制剂 SC58236 治疗可改善转基因小鼠中阿霉素诱导的白蛋白尿。 SC58236 还减少了 COX-2 转基因小鼠和 Balb/C 小鼠中阿霉素诱导的足突消失。因此，COX-2 的过度表达可能会使足细胞进一步损伤。
Increased podocyte cyclooxygenase-2 (COX-2) expression is seen in rats after renal ablation and Thy-1 nephritis and in cultured murine podocytes in response to mechanical stress. For investigation of whether COX-2 overexpression plays a role in podocyte injury, transgenic B6/D2 mice in which COX-2 expression was driven by a nephrin promoter were established. Selective upregulation of COX-2 expression in podocytes of transgenic mouse kidneys was confirmed by immunoblotting and immunohistochemistry. Whether upregulation of podocyte-specific COX-2 expression enhanced sensitivity to the development of Adriamycin nephropathy was examined. Adriamycin administration induced dramatically more albuminuria and foot process effacement and reduced glomerular nephrin mRNA and immunoreactivity in transgenic mice compared with wild-type littermates. Adriamycin also markedly increased immunoreactive COX-2 expression in podocytes from transgenic mice compared with the wild-type mice. Reverse transcriptase-PCR indicated that this increase represented a stimulation of endogenous COX-2 mRNA expression rather than COX-2 mRNA driven by the nephrin promoter. Balb/C mice, which are susceptible to renal injury by Adriamycin, also increased podocyte COX-2 expression and reduced nephrin expression in response to administration of the drug. Long-term treatment with the COX-2-specific inhibitor SC58236 ameliorated the albuminuria that was induced by Adriamycin in the transgenic mice. SC58236 also reduced Adriamycin-induced foot process effacement in both the COX-2 transgenic mice and Balb/C mice. Therefore, overexpression of COX-2 may predispose podocytes to further injury.