Increased renin production in mice with deletion of peroxisome proliferator-activated receptor-gamma in juxtaglomerular cells.
Increased renin production in mice with deletion of peroxisome proliferator-activated receptor-gamma in juxtaglomerular cells.
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DOI：
10.1161/hypertensionaha.109.138800
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发表时间：
2010-03
期刊：
影响因子：
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通讯作者：
Todorov VT
中科院分区：
文献类型：
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作者：
Desch M;Schreiber A;Schweda F;Madsen K;Friis UG;Weatherford ET;Sigmund CD;Sequeira Lopez ML;Gomez RA;Todorov VT
我们最近发现，核受体过氧化物酶体增殖物激活受体-γ (PPARγ)的内源性（游离脂肪酸）和药理学（噻唑烷二酮类）激动剂刺激肾素转录。此外，肾素基因被确定为PPARγ的直接靶点。小鼠肾素基因受PPARγ通过与共识PPAR反应元件（PPRE）密切相关的远端增强子直接重复调控。体外研究表明，PPARγ敲低可刺激ppre驱动的转录。这些数据预测PPARγ缺乏会上调小鼠肾素的表达。与这些观察结果一致的是，在体外，敲低PPARγ增加了小鼠肾素ppre样基序驱动的报告基因的转录。为了研究PPARγ对体内肾素产生的影响，我们使用cre/lox系统培养了双转基因小鼠（RC-PPARγfl/fl小鼠），该小鼠在肾素产生的肾小球旁细胞（JG）中破坏了PPARγ位点。我们提供的证据表明，在RC-PPARγfl/fl小鼠的JG细胞中，PPARγ的表达有效降低。荧光 免疫组织化学显示更强的肾素信号 比同窝出生仔畜RC-PPARγ/ fl控制 RC-PPARγwt / wt老鼠。RC-PPARγfl/fl小鼠肾素mRNA水平和血浆肾素浓度几乎比同窝对照高2倍。在肾素产生调节中起决定性作用的动脉血压和肾血管阻力的压力控制在RC-PPARγwt/wt和RC-PPARγfl/fl小鼠之间无明显差异。这些数据表明，jg特异性PPARγ缺乏导致小鼠体内肾素表达增加，从而证实了早期的体外结果。PPARγ可能是JG细胞中肾素基因调控的相关转录因子。
We found recently that endogenous (free fatty acids) and pharmacological (thiazolidinediones) agonists of nuclear receptor Peroxisome Proliferator-Activated Receptor-γ (PPARγ) stimulate renin transcription. In addition, the renin gene was identified as a direct target of PPARγ. The mouse renin gene is regulated by PPARγ through a distal enhancer direct repeat closely related to consensus PPAR response element (PPRE). In vitro studies demonstrated that PPARγ knockdown stimulated PPRE-driven transcription. These data predicted that deficiency of PPARγ would up-regulate mouse renin expression. Consistent with these observations knockdown of PPARγ increased the transcription of a reporter gene driven by the mouse renin PPRE-like motif in vitro. To study the impact of PPARγ on renin production in vivo we used a cre/lox system to generate double-transgenic mice with disrupted PPARγ locus in renin-producing juxtaglomerular (JG) cells of the kidney (RC-PPARγfl/fl mice). We provide evidence that PPARγ expression was effectively reduced in JG cells of RC-PPARγfl/fl mice. Fluorescent immunohistochemistry showed stronger renin signal in RC-PPARγfl/fl than in littermate control RC-PPARγwt/wt mice. Renin mRNA levels and plasma renin concentration in RC-PPARγfl/fl mice were almost two fold higher than in littermate controls. Arterial blood pressure and pressure control of renal vascular resistance, which play decisive roles in the regulation of renin production were indistinguishable between RC-PPARγwt/wt and RC-PPARγfl/fl mice. These data demonstrate that the JG-specific PPARγ deficiency results in increased mouse renin expression in vivo thus corroborating earlier in vitro results. PPARγ appears to be a relevant transcription factor for the control of renin gene in JG cells.