PMID- 23418489
OWN - NLM
STAT- MEDLINE
DCOM- 20130809
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 2
DP  - 2013
TI  - Protective effects of the mTOR inhibitor everolimus on cytoskeletal injury in 
      human podocytes are mediated by RhoA signaling.
PG  - e55980
LID - 10.1371/journal.pone.0055980 [doi]
LID - e55980
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.
FAU - Jeruschke, Stefanie
AU  - Jeruschke S
AD  - Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, 
      Germany.
FAU - Buscher, Anja Katrin
AU  - Buscher AK
FAU - Oh, Jun
AU  - Oh J
FAU - Saleem, Moin Ahson
AU  - Saleem MA
FAU - Hoyer, Peter Friedrich
AU  - Hoyer PF
FAU - Weber, Stefanie
AU  - Weber S
FAU - Nalbant, Perihan
AU  - Nalbant P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130213
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Immunosuppressive Agents)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 3.6.5.2 (rhoA GTP-Binding Protein)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Apoptosis/drug effects/physiology
MH  - Cell Adhesion/drug effects/physiology
MH  - Cell Movement/drug effects/physiology
MH  - Cells, Cultured
MH  - Cytoskeleton/*drug effects/metabolism
MH  - Everolimus
MH  - Humans
MH  - Immunosuppressive Agents/*pharmacology
MH  - Podocytes/*drug effects/metabolism
MH  - Signal Transduction/*drug effects
MH  - Sirolimus/*analogs & derivatives/pharmacology
MH  - Stress Fibers/drug effects/metabolism
MH  - rhoA GTP-Binding Protein/*metabolism
PMC - PMC3572151
COIS- Competing Interests: The authors declare they have received financial support 
      from Novartis Pharmaceuticals (Basic Research Grant). This does not alter the 
      authors' adherence to all the PLOS ONE policies on sharing data and materials. No 
      other commercial funding was acquired. No other relevant agreements relating to 
      employment, consultancy, patents, products in development or marketed products 
      etc. have been stipulated with Novartis or any other pharmaceutical company.
EDAT- 2013/02/19 06:00
MHDA- 2013/08/10 06:00
PMCR- 2013/02/13
CRDT- 2013/02/19 06:00
PHST- 2012/09/05 00:00 [received]
PHST- 2013/01/04 00:00 [accepted]
PHST- 2013/02/19 06:00 [entrez]
PHST- 2013/02/19 06:00 [pubmed]
PHST- 2013/08/10 06:00 [medline]
PHST- 2013/02/13 00:00 [pmc-release]
AID - PONE-D-12-27377 [pii]
AID - 10.1371/journal.pone.0055980 [doi]
PST - ppublish
SO  - PLoS One. 2013;8(2):e55980. doi: 10.1371/journal.pone.0055980. Epub 2013 Feb 13.