title: 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.
abstract: 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-β1 (TGF-β1), α-smooth muscle actin (α-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-β1, α-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-β1, α-SMA, and secreted Col 3 and decreased E-cadherin. Furthermore, we confirmed that inhibition of the TGF-β1 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-β1 upregulation and ECM deposition through activation of the PI3K/Akt pathway in renal tubular cells. J. Cell. Biochem. 118: 2271-2284, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Shuxia
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Duan
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases / Q000235:genetics / Q000378:metabolism*; D007684:Kidney Tubules / Q000166:cytology*; D009025:Morpholines / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D015820:Cadherins; D002867:Chromones; D004149:Dioxoles; D009025:Morpholines; D053773:Transforming Growth Factor beta1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D005947:Glucose
keywords: DIABETIC MICE; EXTRACELLULAR MATRIX; PHOSPHATIDYLINOSITOL 3-KINASE/PROTEIN KINASE B; RENAL TUBULAR CELLS; SRC HOMOLOGY 2 DOMAIN-CONTAINING INOSITOL 5’-PHOSPHATASE; TRANSFORMING GROWTH FACTOR-β1