Renin cells with defective Gsα/cAMP signaling contribute to renal endothelial damage
Renin cells with defective Gsα/cAMP signaling contribute to renal endothelial damage
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DOI：
10.1007/s00424-019-02298-9
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发表时间：
2019-09-01
影响因子：
4.5
通讯作者：
Todorov, Vladimir T.
中科院分区：
文献类型：
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作者：
Steglich, Anne;Kessel, Friederike;Todorov, Vladimir T.
在肾肾素产生细胞（RPC）中，肾素的合成通过细胞内信使cAMP控制。通过诱导型敲除成年小鼠RPC中的Gs-α（Gs α）干扰cAMP介导的信号传导，导致复杂的不良肾脏表型。其中，肾小球内皮损伤最为显著。在这项研究中，我们研究了Gs α基因敲除是否会导致RPC的丢失，这本身可能会导致内皮损伤。我们比较了连续诱导重组过程中三个RPC特异性条件小鼠系的肾脏表型。在RPC中表达红色荧光报告蛋白tdTomato（tdT）的小鼠作为对照。tdT也在所用的其他两种菌株的RPC中表达，即具有RPC特异性Gs α敲除（Gs α小鼠）或具有RPC特异性白喉毒素A表达（DTA小鼠，其中RPC应该减少）。使用免疫组织学分析，我们发现与对照组相比，Gs α小鼠肾脏中的RPC减少了82%。然而，两种菌株中tdT阳性细胞的数量相似，表明Gs α敲除后，RPC作为肾素阴性后代持续存在。相比之下，在DTA小鼠中，肾素阳性和tdT标记的细胞减少了80%，表明有效的RPC消融。只有Gs α小鼠显示出异常调节的内皮细胞标志物表达，表明肾小球内皮损伤。此外，在从Gs α小鼠分离的tdT标记的RPC中鉴定了参与微血管损伤的组织重塑的基因的强诱导。我们的结论是，Gs α/肾素双阴性RPC后代基本上有助于我们的Gs α缺陷小鼠肾小球内皮损伤的发展。
Synthesis of renin in renal renin-producing cells (RPCs) is controlled via the intracellular messenger cAMP. Interference with cAMP-mediated signaling by inducible knockout of Gs-alpha (Gs alpha) in RPCs of adult mice resulted in a complex adverse kidney phenotype. Therein, glomerular endothelial damage was most striking. In this study, we investigated whether Gs alpha knockout leads to a loss of RPCs, which itself may contribute to the endothelial injury. We compared the kidney phenotype of three RPC-specific conditional mouse lines during continuous induction of recombination. Mice expressing red fluorescent reporter protein tdTomato (tdT) in RPCs served as controls. tdT was also expressed in RPCs of the other two strains used, namely with RPC-specific Gs alpha knockout (Gs alpha mice) or with RPC-specific diphtheria toxin A expression (DTA mice, in which the RPCs should be diminished). Using immunohistological analysis, we found that RPCs decreased by 82% in the kidneys of Gs alpha mice as compared with controls. However, the number of tdT-positive cells was similar in the two strains, demonstrating that after Gs alpha knockout, the RPCs persist as renin-negative descendants. In contrast, both renin-positive and tdT-labeled cells decreased by 80% in DTA mice suggesting effective RPC ablation. Only Gs alpha mice displayed dysregulated endothelial cell marker expression indicating glomerular endothelial damage. In addition, a robust induction of genes involved in tissue remodelling with microvascular damage was identified in tdT-labeled RPCs isolated from Gs alpha mice. We concluded that Gs alpha/renin double-negative RPC progeny essentially contributes for the development of glomerular endothelial damage in our Gs alpha-deficient mice.