Lipid phosphatase SHIP2 downregulates insulin signalling in podocytes

Mervi E. Hyvönen (1) , Pauliina Saurus (1) , Anita Wasik (1) , Eija Heikkilä (1) , Marika Havana (1) , Ras Trokovic (2) , Moin Saleem (3) , Harry Holthöfer (4, 5) , Sanna Lehtonen (1)

1 Department of Pathology
2 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
3 Southmead Hospital
4 Department of Bacteriology and Immunology [Helsinki]
5 DCU - Dublin City University [Dublin]

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.

Mots clés: diabetes; diabetic nephropathy; insulin resistance; podocyte; proteinuria

Mervi E. Hyvönen, Pauliina Saurus, Anita Wasik, Eija Heikkilä, Marika Havana, et al.. Lipid phosphatase SHIP2 downregulates insulin signalling in podocytes. Molecular and Cellular Endocrinology, 2010, 328 (1-2), pp.70. ⟨10.1016/j.mce.2010.07.016⟩. ⟨hal-00618906⟩