PMID- 24392227
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20140106
LR  - 20211021
IS  - 2090-214X (Print)
IS  - 2090-2158 (Electronic)
VI  - 2013
DP  - 2013
TI  - Constitutional Nephrin Deficiency in Conditionally Immortalized Human Podocytes 
      Induced Epithelial-Mesenchymal Transition, Supported by beta-Catenin/NF-kappa B 
      Activation: A Consequence of Cell Junction Impairment?
PG  - 457490
LID - 10.1155/2013/457490 [doi]
LID - 457490
AB  - The kidney glomerular podocytes are the cellular target of many chronic 
      nephropathies both determined and acquired genetically. Mutations that affected 
      the expression and/or the function of nephrin, a key component of the 
      slit-diaphragm, are often causes of these pathologies. Recent findings showed 
      that murine podocytes could undergo epithelial-mesenchymal transformation (EMT), 
      suggesting new hypotheses about the pathogenesis of glomerular fibrosis. Here, we 
      show that also human podocytes can undergo EMT, but more importantly nephrin 
      ablation itself can trigger this phenotypic transformation. In fact, a model of 
      human podocyte with engineered nephrin deficiency constitutionally expressed high 
      levels of alpha-SMA, vimentin, fibronectin, and other hallmarks of EMT. Since it is 
      known that cell contact abrogation is one of the triggers of EMT, we reasoned 
      that nephrin loss could account for such cell junction disruption and cause the 
      EMT. Therefore, we demonstrated that also normal podocytes could spontaneously 
      undergo EMT if grown in Ca(2+)-free medium, which is known to impair cell 
      contacts. The analysis of the main intracellular signal transduction pathways 
      evidenced some major anomalies consequent with the nephrin abrogation. The most 
      intriguing was the activation of beta-catenin pathway, which plays a critical role 
      in podocyte ontogenesis as well as in the nephrin expression and EMT regulation. 
      Also other important signaling proteins, like NF-kappaB, p53, and retinoblastoma 
      protein (RB), showed important activity modifications. Interestingly, most of the 
      above indicated signaling pathway alterations were again reproducible by cell 
      junction rupture, induced by Ca(2+) deprivation. Finally, immunofluorescence 
      analysis on kidney sections of patients with NS of Finnish type confirmed the 
      constitutive expression of alpha-SMA.
FAU - Ghiggeri, Gian Marco
AU  - Ghiggeri GM
AD  - Department of Nephrology, Gaslini Children Hospital, Genoa, Italy.
FAU - Gigante, Maddalena
AU  - Gigante M
AD  - Department of Biomedical Sciences, Interdepartmental Research Center BIOAGROMED, 
      University of Foggia, Italy.
FAU - Di Donato, Armando
AU  - Di Donato A
AD  - Department of Nephrology, Gaslini Children Hospital, Genoa, Italy ; Laboratorio 
      di Nefrologia, Istituto G. Gaslini, Largo G. Gaslini 5, 16147 Genova, Italy.
LA  - eng
PT  - Journal Article
DEP - 20131124
PL  - United States
TA  - Int J Nephrol
JT  - International journal of nephrology
JID - 101546753
PMC - PMC3874297
EDAT- 2014/01/07 06:00
MHDA- 2014/01/07 06:01
PMCR- 2013/11/24
CRDT- 2014/01/07 06:00
PHST- 2013/07/11 00:00 [received]
PHST- 2013/09/11 00:00 [accepted]
PHST- 2014/01/07 06:00 [entrez]
PHST- 2014/01/07 06:00 [pubmed]
PHST- 2014/01/07 06:01 [medline]
PHST- 2013/11/24 00:00 [pmc-release]
AID - 10.1155/2013/457490 [doi]
PST - ppublish
SO  - Int J Nephrol. 2013;2013:457490. doi: 10.1155/2013/457490. Epub 2013 Nov 24.