title: Lipid phosphatase SHIP2 downregulates insulin signalling in podocytes.
abstract: 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.
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Mervi E
authors.initials: ME
authors.lastname: Hyvönen
authors.forename: Pauliina
authors.initials: P
authors.lastname: Saurus
authors.forename: Anita
authors.initials: A
authors.lastname: Wasik
authors.forename: Eija
authors.initials: E
authors.lastname: Heikkilä
authors.forename: Marika
authors.initials: M
authors.lastname: Havana
authors.forename: Ras
authors.initials: R
authors.lastname: Trokovic
authors.forename: Moin
authors.initials: M
authors.lastname: Saleem
authors.forename: Harry
authors.initials: H
authors.lastname: Holthöfer
authors.forename: Sanna
authors.initials: S
authors.lastname: Lehtonen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050199:Podocytes / Q000378:metabolism* / Q000502:physiology; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D011924:Rats, Zucker; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D007328:Insulin; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases