Collecting duct-specific deletion of peroxisome proliferator-activated receptor γ blocks thiazolidinedione-induced fluid retention
Collecting duct-specific deletion of peroxisome proliferator-activated receptor γ blocks thiazolidinedione-induced fluid retention
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DOI：
10.1073/pnas.0501744102
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发表时间：
2005-06-28
影响因子：
11.1
通讯作者：
Yang, TX
中科院分区：
文献类型：
--
作者：
Zhang, H;Zhang, AH;Yang, TX
过氧化物酶体增殖物激活受体亚型γ(PPARγ)配体，即人工合成的胰岛素增敏的噻唑烷二酮(TZD)化合物，在治疗II型糖尿病方面显示出巨大的潜力。然而，它们的临床适用性受到常见且严重的水肿症副作用的限制。为了解决TZD引起的水肿的机制，我们用集合管(CD)特异性破坏PPARγ基因的小鼠作为实验动物。我们发现，CID基因敲除该受体的小鼠对罗格列酮(RGZ)诱导的体重增加和血浆容量扩张具有抵抗力，在CID中表达PPARγ的对照小鼠中发现了这种情况。RGZ减少了对照组和条件性基因敲除小鼠的尿钠排泄。此外，RGZ刺激原代培养的表达PPARγ的CD细胞的钠转运，而不是缺乏这种受体的细胞。这些发现表明，在TZD诱导的液体滞留的基础上，PPAR伽马依赖的途径调节CD中的钠运输。
The peroxisome proliferator-activated receptor subtype gamma (PPAR gamma) ligands, namely the synthetic insulin-sensitizing thiazolidinedione (TZD) compounds, have demonstrated great potential in the treatment of type II diabetes. However, their clinical applicability is limited by a common and serious side effect of edema. To address the mechanism of TZD-induced edema, we generated mice with collecting duct (CD)-specific disruption of the PPAR gamma gene. We found that mice with CID knockout of this receptor were resistant to the rosiglitazone- (RGZ) induced increases in body weight and plasma volume expansion found in control mice expressing PPAR gamma in the CID. RGZ reduced urinary sodium excretion in control and not in conditional knockout mice. Furthermore, RGZ stimulated sodium transport in primary cultures of CD cells expressing PPAR gamma and not in cells lacking this receptor. These findings demonstrate a PPAR gamma- dependent pathway in regulation of sodium transport in the CD that underlies TZD-induced fluid retention.