Src Homology 2 Domain-Containing Inositol 5-Phosphatase Ameliorates High Glucose-Induced Extracellular Matrix Deposition via the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway in Renal Tubular Epithelial Cells
Src Homology 2 Domain-Containing Inositol 5-Phosphatase Ameliorates High Glucose-Induced Extracellular Matrix Deposition via the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway in Renal Tubular Epithelial Cells
复制标题
含有 Src 同源 2 结构域的肌醇 5-磷酸酶通过肾小管上皮细胞中的磷脂酰肌醇 3-激酶/蛋白激酶 B 途径改善高葡萄糖诱导的细胞外基质沉积
DOI：
10.1002/jcb.25881
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发表时间：
2017-08-01
影响因子：
4
通讯作者：
Duan, Huijun
中科院分区：
文献类型：
--
作者：
Li, Fan;Li, Lisha;Duan, Huijun
糖尿病肾病（DKD）的典型标志是细胞外基质（ECM）在肾小球和肾小管上皮细胞中的过度沉积，导致肾小球硬化和肾小管间质纤维化。含Src同源2结构域的肌醇5-磷酸酶（SHIP）是磷脂酰肌醇3-激酶/蛋白激酶B（PI 3 K/Akt）信号传导的负调节剂。在这里，我们研究了SHIP对糖尿病小鼠和高糖刺激的人肾小管上皮细胞（HK 2细胞）ECM沉积的影响。糖尿病小鼠肾小管上皮细胞SHIP降低，磷酸化Akt（Ser 473，Thr 308）增加，同时伴有转化生长因子1（TGF-1）、平滑肌肌动蛋白（-SMA）和3型胶原（Col 3）的过度表达，E钙粘蛋白（E-cadherin）表达降低。体外研究表明，高糖减弱SHIP表达伴随着PI 3 K/Akt信号通路的激活和ECM的产生。在HK 2细胞中敲低SHIP导致磷酸化Akt（Ser 473）、磷酸化Akt（Thr 308）、TGF-1、-SMA和分泌的Col 3水平增加，并且E-钙粘蛋白减少。同样，M90-SHIP质粒或PI 3 K/Akt通路抑制剂LY 294002可以显著防止高糖诱导的TGF-1、-SMA和分泌Col 3的增加以及E-钙粘蛋白的减少。此外，我们证实了用SB 431542抑制TGF-1通路阻断了SHIP敲低对HK 2细胞中ECM产生的影响。总之，我们的研究表明，降低SHIP介导高糖诱导的TGF-1上调和ECM沉积通过激活PI 3 K/Akt途径在肾小管细胞。J.细胞。118：2271-2284，2017. (c)2017 Wiley Periodicals，Inc.
A typical hallmark of diabetic kidney disease (DKD) is an excessive deposition of extracellular matrix (ECM) in the glomerulus and renal tubulointerstitium, leading to glomerulosclerosis and tubular interstitial fibrosis. Src homology 2 domain-containing inositol 5-phosphatase (SHIP) is a negative regulator of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling. Here, we investigated the effect of SHIP on ECM deposition in diabetic mice and high glucose-stimulated human renal tubular epithelial cells (HK2 cells). The decreased SHIP and increased phospho-Akt (Ser 473, Thr 308) were found in the renal tubular cells of diabetic mice, which were accompanied by overexpression of transforming growth factor-1 (TGF-1), -smooth muscle actin (-SMA), and secreted collagen type 3 (Col 3) and a low expression of E-cadherin compared to that in normal mice. In vitro research revealed that high glucose-attenuated SHIP expression accompanied the activation of the PI3K/Akt signaling and ECM production. Knocking down SHIP in HK2 cells caused an increase in the levels of phospho-Akt (Ser 473), phospho-Akt (Thr 308), TGF-1, -SMA, and secreted Col 3 and a decrease in E-cadherin. Again, either the M90-SHIP plasmid or the PI3K/Akt pathway inhibitor LY294002 could significantly prevent the high glucose-induced increase in TGF-1, -SMA, and secreted Col 3 and decreased E-cadherin. Furthermore, we confirmed that inhibition of the TGF-1 pathway with SB431542 blocked the effect of SHIP knockdown on ECM production in HK2 cells. In summary, our study suggests that decreased SHIP mediates high glucose-induced TGF-1 upregulation and ECM deposition through activation of the PI3K/Akt pathway in renal tubular cells. J. Cell. Biochem. 118: 2271-2284, 2017. (c) 2017 Wiley Periodicals, Inc.