title: SHIP, a novel factor to ameliorate extracellular matrix accumulation via suppressing PI3K/Akt/CTGF signaling in diabetic kidney disease.
abstract: Tubular interstitial extracellular matrix accumulation, which plays a key role in the pathogenesis and progression of diabetic kidney disease (DKD), is believed to be mediated by activation of PI3K/Akt signal pathway. However, it is still not clear whether SH2 domain-containing inositol 5'-phosphatase (SHIP), known as a negative regulator of PI3K/Akt pathway is also involved in extracellular matrix metabolism of diabetic kidney. In the present study, decreased SHIP and increased phospho-Akt (Ser 473, Thr 308) were found in renal tubular cells of diabetic mice accompanied by overexpression of connective tissue growth factor (CTGF) and extracellular matrix deposition versus normal mice. Again, high glucose attenuated SHIP expression in a time-dependent manner, concomitant with activation of PI3K/Akt signaling and extracellular matrix production in human renal proximal tubular epithelial cells (HK2) cultured in vitro, which was significantly prevented by transfection of M90-SHIP vector. Furthermore, in vivo delivery of rAd-INPP5D vector (SHIP expression vector) via intraperitoneal injection in diabetic mice increased SHIP expression by 3.36 times followed by 65.26%, 70.38% and 46.71% decreases of phospho-Akt (Ser 473), phospho-Akt (Thr 308) and CTGF expression versus diabetic mice receiving rAd-EGFP vector. Meanwhile, increased renal extracellular matrix accumulation of diabetic mice was also inhibited with intraperitoneal injection of rAd-INPP5D vector. These above data suggested that overexpression of SHIP might be a potent method to lessen renal extracellular matrix accumulation via inactivation of PI3K/Akt pathway and suppression of CTGF expression in DKD.
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Shuxia
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei, China. Electronic address: duanhuijun@hotmail.com.
authors.forename: Huijun
authors.initials: H
authors.lastname: Duan
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D003094:Collagen; D024042:Collagen Type I; D055513:Connective Tissue Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D051057:Proto-Oncogene Proteins c-akt; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; C494918:AKT1 protein, human; C514862:Akt1 protein, mouse; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse
keywords: Diabetic kidney disease; Extracellular matrix; PI3K/Akt; Renal tubular cell; SHIP