TY - JOUR
T1 - Cellular effects of Everolimus and Sirolimus on podocytes
AU - Müller-Krebs, Sandra
AU - Weber, Lena
AU - Tsobaneli, Julia
AU - Kihm, Lars P.
AU - Reiser, Jochen
AU - Zeier, Martin
AU - Schwenger, Vedat
N1 - Funding Information:
SMK, MZ, and VS received research grants from Novartis Pharma AG (Nuremberg, Germany). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. MZ and VS received lecture fees from Novartis Pharma AG (Nuremberg, Germany). The authors declare no competing interests relating to consultancy, patents, products in development or marketed products. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
PY - 2013/11/15
Y1 - 2013/11/15
N2 - Everolimus (EVL) and Sirolimus (SRL) are potent immunosuppressant agents belonging to the group of mammalian target of rapamycin (mTOR) inhibitors used to prevent transplant rejection. However, some patients develop proteinuria following a switch from a calcineurin inhibitor regimen to mTOR inhibitors. Whether different mTOR inhibitors show similar effects on podocytes is still unknown. To analyze this, human podocytes were incubated with different doses of EVL and SRL. After incubation with EVL or SRL, podocytes revealed a reduced expression of total mTOR. Phosphorylation of p70S6K and Akt was diminished, whereas pAkt expression was more reduced in the SRL group. In both groups actin cytoskeletal reorganization was increased. Synaptopodin and podocin expression was reduced as well as nephrin protein, particularly in the SRL group. NFκB activation and IL-6 levels were lower in EVL and SRL, and even lower in SRL. Apoptosis was more increased in SRL than in the EVL group. Our data suggests that mTOR inhibitors affect podocyte integrity with respect to podocyte proteins, cytoskeleton, inflammation, and apoptosis. Our study is the first to analyze both mTOR inhibitors, EVL and SRL, in parallel in podocytes. Partially, the impact of EVL and SRL on podocytes differs. Nevertheless, it still remains unclear whether these differences are of relevance regarding to proteinuria in transplant patients.
AB - Everolimus (EVL) and Sirolimus (SRL) are potent immunosuppressant agents belonging to the group of mammalian target of rapamycin (mTOR) inhibitors used to prevent transplant rejection. However, some patients develop proteinuria following a switch from a calcineurin inhibitor regimen to mTOR inhibitors. Whether different mTOR inhibitors show similar effects on podocytes is still unknown. To analyze this, human podocytes were incubated with different doses of EVL and SRL. After incubation with EVL or SRL, podocytes revealed a reduced expression of total mTOR. Phosphorylation of p70S6K and Akt was diminished, whereas pAkt expression was more reduced in the SRL group. In both groups actin cytoskeletal reorganization was increased. Synaptopodin and podocin expression was reduced as well as nephrin protein, particularly in the SRL group. NFκB activation and IL-6 levels were lower in EVL and SRL, and even lower in SRL. Apoptosis was more increased in SRL than in the EVL group. Our data suggests that mTOR inhibitors affect podocyte integrity with respect to podocyte proteins, cytoskeleton, inflammation, and apoptosis. Our study is the first to analyze both mTOR inhibitors, EVL and SRL, in parallel in podocytes. Partially, the impact of EVL and SRL on podocytes differs. Nevertheless, it still remains unclear whether these differences are of relevance regarding to proteinuria in transplant patients.
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U2 - 10.1371/journal.pone.0080340
DO - 10.1371/journal.pone.0080340
M3 - Article
C2 - 24260371
AN - SCOPUS:84894151094
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 11
M1 - e80340
ER -