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mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes

¹Universitätsklinikum Münster, Medizinische Klinik und Poliklinik D, Münster, Germany; and ²Academic and Children's Renal Unit, University of Bristol, Bristol, United Kingdom

Submitted 19 May 2008 ; accepted in final form 17 November 2008

The immunosuppressive mammalian target of rapamycin (mTOR) inhibitors can cause proteinuria, especially in kidney and heart transplanted patients. Podocytes play a major role in establishing the selective permeability of the blood-urine filtration barrier. Damage of these cells leads to proteinuria, a hallmark of most glomerular diseases. Interestingly, podocyte damage and focal segmental glomerulosclerosis can occur after treatment with an mTOR inhibitor in some transplant patients. To investigate the mechanisms of mTOR inhibitor-induced podocyte damage, we analyzed the effect of rapamycin on mTOR signaling and cellular function in human podocytes. We found that prolonged rapamycin treatment reduced the expression of total mTOR, which correlates with diminished levels of mTOR phosphorylation at Ser²⁴⁴⁸ and Ser²⁴⁸¹. In addition, treatment with rapamycin reduced rictor expression and mTORC2 formation, resulting in a reduced phosphorylation of protein kinase B at Ser⁴⁷³. The expression level of the slit-diaphragm proteins nephrin and transient receptor potential cation channel 6 as well as the cytoskeletal adaptor protein Nck significantly decreased. Moreover, rapamycin reduced cell adhesion and cell motility, which was accompanied by an enhanced formation of dot-like actin-rich structures. Our data provide new molecular insights explaining which pathways and molecules are affected in podocytes by an imbalanced mTOR function because of rapamycin treatment.

sirolimus; proteinuria; slit diaphragm; mammalian target of rapamycin

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