肾脏 SNX5 的缺失导致小鼠 IDE 活性受损和胰岛素抵抗。
Loss of renal SNX5 results in impaired IDE activity and insulin resistance in mice.
机构信息
Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, DC, USA.
Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
出版信息
Diabetologia. 2018 Mar;61(3):727-737. doi: 10.1007/s00125-017-4482-1. Epub 2017 Oct 28.
AIMS/HYPOTHESIS: We 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.
METHODS
The regulation of IDE by SNX5 expressed in the kidney was studied in vitro and in vivo. Snx5 or 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.
RESULTS
SNX5 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. Silencing SNX5 in hRPTCs decreased IDE expression and activity. Renal-selective silencing of Snx5 (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. Kidney Snx5-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/INTERPRETATION: Renal 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.
目的/假设：我们假设肾分选连接蛋白 5（SNX5）调节胰岛素降解酶（IDE），从而调节循环胰岛素水平。因此，我们研究了 SNX5 和 IDE 在人肾近端小管细胞（hRPTC）中的动态相互作用，以及在大鼠和小鼠肾脏中的相互作用。
方法
在体外和体内研究了 SNX5 在肾脏中对 IDE 的调节作用。在培养的永生化 hRPTC（传代<20）中加入 SNX5 或模拟 siRNA，或通过渗透微型泵选择性输注到单侧肾切除大鼠和小鼠的残肾中。
结果
SNX5 在 hRPTC 的质膜和核周区以及人、大鼠和小鼠肾脏的近端小管刷状缘膜与 IDE 共定位。胰岛素增加了 hRPTC 中 SNX5 和 IDE 的共定位和共免疫沉淀。在 hRPTC 中沉默 SNX5 降低了 IDE 的表达和活性。在 C57Bl/6J 小鼠中，肾脏选择性沉默 Snx5（SNX5 蛋白：100±25 对 29±10，p<0.05[对照的%]）降低了 IDE 蛋白（100±13 对 57±6，p<0.05[对照的%]）和尿胰岛素排泄，损害了对胰岛素和葡萄糖的反应，并增加了血液胰岛素和葡萄糖水平。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 SNX5（100±27 对 29±6，p<0.05[对照的%]）和 IDE（100±5 对 75±4，p<0.05[对照的%]）蛋白减少，与正常血压的 Wistar-Kyoto（WKY）大鼠相比。肾 Snx5 耗竭的 WKY 大鼠的血液胰岛素和葡萄糖水平也升高。与来自正常血压志愿者的细胞相比，SHR 患者和高血压患者的 RPTC 中 SNX5 和 IDE 的表达减少，表明高胰岛素血症和高血压的共同原因。
结论/解释：肾脏 SNX5 正向调节 IDE 的表达和功能。本研究首次证明了肾脏 SNX5 在胰岛素和葡萄糖代谢中的新的关键作用。
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