Lipid phosphatase SHIP2 downregulates insulin signalling in podocytes

MOLECULAR AND CELLULAR ENDOCRINOLOGY

卷:328

Article

Hyvonen, Mervi E.^1,2  Saurus, Pauliina¹  Wasik, Anita¹  Heikkila, Eija¹  Havana, Marika¹  Trokovic, Ras³  Saleem, Moin⁴  Holthofer, Harry^5,6  Lehtonen, Sanna¹ 

[1] Univ Helsinki, Haartman Inst, Dept Pathol, FIN-00014 Helsinki, Finland

[2] Univ Helsinki, Hosp Children & Adolescents, FIN-00014 Helsinki, Finland

[3] Univ Helsinki, Program Mol Neurol, Biomedicum Stem Cell Ctr, FIN-00014 Helsinki, Finland

[4] Univ Bristol, Acad & Childrens Renal Unit, Southmead Hosp, Bristol, Avon, England

[5] Univ Helsinki, Haartman Inst, Dept Bacteriol & Immunol, FIN-00014 Helsinki, Finland

[6] Dublin City Univ, Dublin 9, Ireland

关键词: Diabetes;    Diabetic nephropathy;    Insulin resistance;    Podocyte;    Proteinuria;   

DOI  :  10.1016/j.mce.2010.07.016

来源: Elsevier

【 摘 要 】

Podocyte injury plays an important role in the development of diabetic nephropathy. Podocytes are insulin-responsive and can develop insulin resistance, but the mechanisms are unknown. To study the role of CD2-associated protein (CD2AP) in podocyte injury, we performed a yeast two-hybrid screening on a glomerular library, and found that CD2AP bound to SH2-domain-containing inositol polyphosphate 5-phosphatase 2 (SHIP2), a negative regulator of insulin signalling. SHIP2 interacts with CD2AP in glomeruli and is expressed in podocytes, where it translocates to plasma membrane after insulin stimulation. Overexpression of SHIP2 in cultured podocytes reduces Akt activation in response to insulin, and promotes apoptosis. SHIP2 is upregulated in glomeruli of insulin resistant obese Zucker rats. These results indicate that SHIP2 downregulates insulin signalling in podocytes. The upregulation of SHIP2 in Zucker rat glomeruli prior to the age of onset of proteinuria suggests a possible role for SHIP2 in the development of podocyte injury. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

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