BACKGROUND: The specific mTor inhibitor sirolimus has been implicated in the pathogenesis of renal glomerular lesions and nephrotic syndrome appearance after transplantation. Podocyte injury and focal segmental glomerulosclerosis have been related to sirolimus therapy in some patients but the pathways underlying these lesions remain hypothetical. METHODS: To go further in the comprehension of these mechanisms, primary cultures of human podocytes were exposed to therapeutic-range concentrations of sirolimus. RESULTS: Cell viability was not affected after 2 days' exposure to the drug but changes in cell phenotype and cytoskeleton reorganization were observed. We also evidenced that vascular endothelial growth factor (VEGF) synthesis and Akt phosphorylation were decreased by sirolimus addition. We did not observe any loss of podocyte differentiation markers with the notable exception of WT1, a transcription factor essential for maintaining podocyte integrity. WT1 gene and protein expression in podocytes were decreased in a dose-dependent manner after incubation with sirolimus. CONCLUSION: Taken together, these data suggest that sirolimus could impair pathways essential for podocyte integrity and therefore predisposes to glomerular injury.
BACKGROUND: The specific mTor inhibitor sirolimus has been implicated in the pathogenesis of renal glomerular lesions and nephrotic syndrome appearance after transplantation. Podocyte injury and focal segmental glomerulosclerosis have been related to sirolimus therapy in some patients but the pathways underlying these lesions remain hypothetical. METHODS: To go further in the comprehension of these mechanisms, primary cultures of human podocytes were exposed to therapeutic-range concentrations of sirolimus. RESULTS: Cell viability was not affected after 2 days' exposure to the drug but changes in cell phenotype and cytoskeleton reorganization were observed. We also evidenced that vascular endothelial growth factor (VEGF) synthesis and Akt phosphorylation were decreased by sirolimus addition. We did not observe any loss of podocyte differentiation markers with the notable exception of WT1, a transcription factor essential for maintaining podocyte integrity. WT1 gene and protein expression in podocytes were decreased in a dose-dependent manner after incubation with sirolimus. CONCLUSION: Taken together, these data suggest that sirolimus could impair pathways essential for podocyte integrity and therefore predisposes to glomerular injury.
Authors: Guillaume Canaud; Frank Bienaimé; Amandine Viau; Caroline Treins; William Baron; Clément Nguyen; Martine Burtin; Sophie Berissi; Konstantinos Giannakakis; Andrea Onetti Muda; Stefan Zschiedrich; Tobias B Huber; Gérard Friedlander; Christophe Legendre; Marco Pontoglio; Mario Pende; Fabiola Terzi Journal: Nat Med Date: 2013-09-22 Impact factor: 53.440
Authors: Vicente E Torres; Alessandra Boletta; Arlene Chapman; Vincent Gattone; York Pei; Qi Qian; Darren P Wallace; Thomas Weimbs; Rudolf P Wüthrich Journal: Clin J Am Soc Nephrol Date: 2010-05-24 Impact factor: 8.237
Authors: John Vassiliadis; Christina Bracken; Douglas Matthews; Stephen O'Brien; Susan Schiavi; Stefan Wawersik Journal: J Am Soc Nephrol Date: 2011-07-22 Impact factor: 10.121