Protective effects of the mTOR inhibitor everolimus on cytoskeletal injury in human podocytes are mediated by RhoA signaling
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Protective effects of the mTOR inhibitor everolimus on cytoskeletal injury in human podocytes are mediated by RhoA signaling. / Jeruschke, Stefanie; Büscher, Anja Katrin; Oh, Jun; Saleem, Moin Ahson; Hoyer, Peter Friedrich; Weber, Stefanie; Nalbant, Perihan.
in: PLOS ONE, Jahrgang 8, Nr. 2, 01.01.2013, S. e55980.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Protective effects of the mTOR inhibitor everolimus on cytoskeletal injury in human podocytes are mediated by RhoA signaling
AU - Jeruschke, Stefanie
AU - Büscher, Anja Katrin
AU - Oh, Jun
AU - Saleem, Moin Ahson
AU - Hoyer, Peter Friedrich
AU - Weber, Stefanie
AU - Nalbant, Perihan
PY - 2013/1/1
Y1 - 2013/1/1
N2 - Podocytes are highly differentiated kidney cells playing an important role in maintaining the glomerular filtration barrier. Particularly, the integrity of the actin cytoskeleton is crucial as cytoskeletal damage associated with foot process effacement and loss of slit diaphragms constitutes a major aspect of proteinuria. Previously, the mammalian target of rapamycin (mTOR) was linked to actin regulation and aberrant activity of the kinase was associated with renal disease. In this study, actin-related effects of mTOR inhibition by the immunosuppressant everolimus (EV) were investigated in human podocytes using an in vitro model of puromycin aminonucleoside (PAN) induced proteinuria. EV substantially recovered aberrant podocyte behavior by re-establishing a stationary phenotype with decreased migration efficiency, enhanced cell adhesion and recovery of actin stress fibers. Biochemical studies revealed substantial increase in the activity of RhoA and the effector pathway Rho-associated protein kinase (ROCK) and myosin light chain (MLC) by EV, all known regulators of stress fiber generation. Taken together, we show for the first time cytoskeleton stabilizing effects of the mTOR inhibitor EV and establish RhoA signaling as a key mediator in this process.
AB - Podocytes are highly differentiated kidney cells playing an important role in maintaining the glomerular filtration barrier. Particularly, the integrity of the actin cytoskeleton is crucial as cytoskeletal damage associated with foot process effacement and loss of slit diaphragms constitutes a major aspect of proteinuria. Previously, the mammalian target of rapamycin (mTOR) was linked to actin regulation and aberrant activity of the kinase was associated with renal disease. In this study, actin-related effects of mTOR inhibition by the immunosuppressant everolimus (EV) were investigated in human podocytes using an in vitro model of puromycin aminonucleoside (PAN) induced proteinuria. EV substantially recovered aberrant podocyte behavior by re-establishing a stationary phenotype with decreased migration efficiency, enhanced cell adhesion and recovery of actin stress fibers. Biochemical studies revealed substantial increase in the activity of RhoA and the effector pathway Rho-associated protein kinase (ROCK) and myosin light chain (MLC) by EV, all known regulators of stress fiber generation. Taken together, we show for the first time cytoskeleton stabilizing effects of the mTOR inhibitor EV and establish RhoA signaling as a key mediator in this process.
KW - Apoptosis
KW - Cell Adhesion
KW - Cell Movement
KW - Cells, Cultured
KW - Cytoskeleton
KW - Humans
KW - Immunosuppressive Agents
KW - Podocytes
KW - Signal Transduction
KW - Sirolimus
KW - Stress Fibers
KW - rhoA GTP-Binding Protein
U2 - 10.1371/journal.pone.0055980
DO - 10.1371/journal.pone.0055980
M3 - SCORING: Journal article
C2 - 23418489
VL - 8
SP - e55980
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 2
ER -
