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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

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.