Loss of renal SNX5 results in impaired IDE activity and insulin resistance in mice.
Loss of renal SNX5 results in impaired IDE activity and insulin resistance in mice.
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肾 SNX5 缺失导致小鼠 IDE 活性受损和胰岛素抵抗
DOI：
10.1007/s00125-017-4482-1
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发表时间：
2018-03
期刊：
影响因子：
8.2
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Li F;Yang J;Villar VAM;Asico LD;Ma X;Armando I;Sanada H;Yoneda M;Felder RA;Jose PA;Wang X
目的/假设我们假设肾分选连接蛋白5（SNX 5）调节胰岛素降解酶（IDE），从而调节循环胰岛素水平。方法在体外和体内研究SNX 5对IDE的调控作用，并将SNX 5或模拟siRNA加入到永生化的hRPTC中，观察SNX 5对IDE的调控作用（传代<20）培养或选择性输注，通过渗透微型泵，结果SNX 5与IDE共定位于人肾皮质细胞的质膜、核周区和人近端小管的刷状缘膜，大鼠和小鼠肾脏。胰岛素增加SNX 5和IDE在hRPTC中的共定位和共免疫沉淀。沉默SNX 5可降低IDE的表达和活性。在C57 Bl/6 J小鼠中，肾选择性沉默Snx 5（SNX 5蛋白：100 ± 25 vs 29 ± 10，p< 0.05 [对照%]）降低IDE蛋白（100 ± 13 vs 57 ± 6，p< 0.05 [对照%]）和尿胰岛素排泄，损害对胰岛素和葡萄糖的反应，并增加血液胰岛素和葡萄糖水平。与血压正常的Wistar-Kyoto（WKY）大鼠相比，自发性高血压大鼠（SHR）的血液胰岛素和葡萄糖水平升高，肾脏SNX 5（100 ± 27 vs 29 ± 6，p <0.05 [对照组的%]）和IDE（100 ± 5 vs 75 ± 4，p< 0.05 [对照组的%]）蛋白降低。肾Snx 5缺失的WKY大鼠也具有增加的血液胰岛素和葡萄糖水平。SNX 5和IDE的表达减少RPTC从SHR和高血压的人相比，从正常血压志愿者的细胞，表明一个共同的原因高胰岛素血症和hypertension.Conclusions/interpretationRenal SNX 5正调控IDE的表达和功能。这项研究首次证明了肾脏SNX 5在胰岛素和葡萄糖代谢中的新的关键作用。
Aims/hypothesisWe hypothesised that renal sorting nexin 5 (SNX5) regulates the insulin-degrading enzyme (IDE) and, thus, circulating insulin levels. We therefore studied the dynamic interaction between SNX5 and IDE in human renal proximal tubule cells (hRPTCs), as well as in rat and mouse kidneys.MethodsThe regulation of IDE by SNX5 expressed in the kidney was studied in vitro and in vivo.Snx5or mock siRNA was added to immortalised hRPTCs (passage <20) in culture or selectively infused, via osmotic mini-pump, into the remnant kidney of uninephrectomised mice and rats.ResultsSNX5 co-localised with IDE at the plasma membrane and perinuclear area of hRPTCs and in the brush border membrane of proximal tubules of human, rat, and mouse kidneys. Insulin increased the co-localisation and co-immunoprecipitation of SNX5 and IDE in hRPTCs. SilencingSNX5in hRPTCs decreased IDE expression and activity. Renal-selective silencing ofSnx5(SNX5 protein: 100 ± 25 vs 29 ± 10,p< 0.05 [% of control]) in C57Bl/6J mice decreased IDE protein (100 ± 13 vs 57 ± 6,p< 0.05 [% of control]) and urinary insulin excretion, impaired the responses to insulin and glucose, and increased blood insulin and glucose levels. Spontaneously hypertensive rats (SHRs) had increased blood insulin and glucose levels and decreased renal SNX5 (100 ± 27 vs 29 ± 6,p< 0.05 [% of control]) and IDE (100 ± 5 vs 75 ± 4,p< 0.05 [% of control]) proteins, compared with normotensive Wistar–Kyoto (WKY) rats. KidneySnx5-depleted WKY rats also had increased blood insulin and glucose levels. The expression of SNX5 and IDE was decreased in RPTCs from SHRs and hypertensive humans compared with cells from normotensive volunteers, indicating a common cause for hyperinsulinaemia and hypertension.Conclusions/interpretationRenal SNX5 positively regulates IDE expression and function. This study is the first to demonstrate the novel and crucial role of renal SNX5 in insulin and glucose metabolism.
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DOI：
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发表时间：
2012-12-01
影响因子：
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作者：
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DOI：
10.1016/j.bbrc.2010.10.104
发表时间：
2010-11-26
影响因子：
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