PTEN Regulates Renal Extracellular Matrix Deposit via Increased CTGF in Diabetes Mellitus
PTEN Regulates Renal Extracellular Matrix Deposit via Increased CTGF in Diabetes Mellitus
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PTEN 通过增加糖尿病中的 CTGF 来调节肾细胞外基质沉积
DOI：
10.1002/jcb.25402
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发表时间：
2016-05-01
影响因子：
4
通讯作者：
Hao, Jun
中科院分区：
文献类型：
--
作者：
Zhu, Lin;Zhao, Song;Hao, Jun
细胞外基质积聚和纤维化是糖尿病肾病的特征。磷脂酰肌醇3-激酶（phosphatidylinositol 3-kinase，PI 3 K）/蛋白激酶B（protein kinase B，Akt）信号通路及其抑制剂PTEN（phosphatase and tensin homolog deleted on chromosome 10）在肾纤维化中起重要作用。然而，确切的机制仍不清楚。在本研究中，我们发现，与正常小鼠相比，糖尿病小鼠肾脏中的PTEN减少，磷酸化Akt（Ser 473）、磷酸化Akt（Thr 308）、CTGF（结缔组织生长因子）、α-SMA（α-平滑肌肌动蛋白）和基质细胞蛋白增加。在HKC细胞（人肾小管上皮细胞）中，敲低PTEN引起磷酸化Akt（Ser 473）、磷酸化Akt（Thr 308）、CTGF、分泌的纤连蛋白和分泌的Col 3增加。同样，体外实验显示，与正常对照细胞相比，高糖刺激的HKC细胞中磷酸化Akt（Ser 473）、磷酸化Akt（Thr 308）、CTGF、分泌的纤连蛋白和分泌的Col 3增加了1.89、2.18、1.92、3.06、2.06倍。此外，敲低CTGF逆转了高糖处理的HKC细胞中分泌增加的纤连蛋白和Col 3。此外，转染PTEN表达载体可以防止高糖引起的HKC细胞的这些变化。尤其是CTGF的表达、纤维连接蛋白和Col 3的分泌分别降低了38.81、53.85和39.12%。LY 294002处理抑制磷酸化Akt（Ser 473）和磷酸化Akt（Thr 308）表达，随后降低高糖处理的HKC细胞中的CTGF、分泌型纤连蛋白和分泌型Col 3。最后，我们的研究表明，在糖尿病中，PTEN通过激活Akt和增加CTGF来调节肾脏细胞外基质的产生。(C)2015 Wiley Periodicals，Inc.
Extracellular matrix accumulation and fibrosis are the features of diabetic nephropathy. PI3K (phosphatidylinositol 3-kinase)/Akt (protein kinase B) signal pathway and its inhibitor PTEN (phosphatase and tensin homolog deleted on chromosome 10) are revealed to modulate renal fibrosis. However, the exact mechanism is still not well known. In the present study we found that compared with normal mice, diabetic mice showed decreased PTEN, increased phospho-Akt (Ser 473), phospho-Akt (Thr 308), CTGF (connective tissue growth factor), alpha-SMA (alpha-smooth muscle actin), and matricellular protein in kidney. Knocking down of PTEN caused an increase in phospho-Akt (Ser 473), phospho-Akt (Thr 308), CTGF, secreted fibronectin, and secreted Col 3 in HKC cells (human renal tubular epithelial cells). Again, in vitro experiment revealed 1.89, 2.18, 1.92, 3.06, 2.06-fold increases of phospho-Akt (Ser 473), phospho-Akt (Thr 308), CTGF, secreted fibronectin, and secreted Col 3 in high glucose-stimulated HKC cells in comparison with normal control cells. Furthermore, knocking down of CTGF reversed increased secreted fibronectin and Col 3 in high glucose-treated HKC cells. Moreover, transfection of PTEN expression vector prevented high glucose-caused these changes in HKC cells. Especially, CTGF expression, secretion of fibronectin and Col 3 were, respectively, decreased by 38.81, 53.85, and 39.12%. The treatment of LY294002 inhibited phospho-Akt (Ser 473) and phospho-Akt (Thr 308) expression followed by decreased CTGF, secretory fibronectin and secretory Col 3 in high glucose-treated HKC cells. In the end our study suggests that PTEN regulates renal extracellular matrix production via activated Akt and increased CTGF in diabetes mellitus. (C) 2015 Wiley Periodicals, Inc.