title: Glomerular mRNA expression of prothrombotic and antithrombotic factors in renal transplants with thrombotic microangiopathy.
abstract: BACKGROUND
  Thrombotic microangiopathy (TMA) in renal transplants (rTx-TMA) is a serious complication and is usually either recurrent TMA (RecTMA) due to humoral rejection (HR-TMA) or due to calcineurin inhibitor toxicity (CNI-TMA). Although the triggers are known, our knowledge about the thrombogenic transcriptome changes in the microvessels is rudimentary.
  
  
  METHODS
  We examined the expression of several prothrombotic and antithrombotic genes in 25 biopsies with rTx-TMA (6 RecTMA, 9 HR-TMA, and 10 CNI-TMA) and 8 controls. RNA from microdissected glomeruli of paraffin-embedded tissue was isolated and mRNA transcripts were quantified with real-time polymerase chain reaction after preamplification. Results were correlated with clinicopathologic parameters.
  
  
  RESULTS
  Glomerular mRNA expression of KLF2, KLF4, and tPA was lower and that of PAI-1 was higher in rTx-TMA than in the controls. Glomerular mRNA expression of KLF2 and KLF4 correlated with that of tPA and inversely with that of PAI-1 in rTx-TMA. The mRNA expression of complement regulators CD46 and CD59 were higher in rTx-TMA than in the controls. Only in HR-TMA were glomerular ADAMTS13 and CD55 down-regulated.
  
  
  CONCLUSIONS
  The glomerular capillary bed seems to contribute to all subtypes of rTx-TMA by down-regulation of the endothelial transcription factors KLF2 and KLF4, indicating dedifferentiation with subsequent up-regulation of PAI-1 and down-regulation of tPA, resulting in inhibition of local fibrinolysis. Decreased glomerular expression of ADAMTS13 and CD55 could be an additional pathway toward microthrombosis exclusively in HR-TMA.
authors: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors: Putri Andina
authors: PA
authors: Agustian
authors: Clemens Luitpold
authors: CL
authors: Bockmeyer
authors: Friedrich
authors: F
authors: Modde
authors: Juliane
authors: J
authors: Wittig
authors: Falko Markus
authors: FM
authors: Heinemann
authors: Stephanie
authors: S
authors: Brundiers
authors: Maximilian Ernst
authors: ME
authors: Dämmrich
authors: Anke
authors: A
authors: Schwarz
authors: Ingvild
authors: I
authors: Birschmann
authors: Barbara
authors: B
authors: Suwelack
authors: Peter Thomas
authors: PT
authors: Jindra
authors: Thurid
authors: T
authors: Ahlenstiel
authors: Jeremias
authors: J
authors: Wohlschläger
authors: Udo
authors: U
authors: Vester
authors: Tina
authors: T
authors: Ganzenmüller
authors: Eva
authors: E
authors: Zilian
authors: Thorsten
authors: T
authors: Feldkamp
authors: Tilmann
authors: T
authors: Spieker
authors: Stephan
authors: S
authors: Immenschuh
authors: Hans Heinrich
authors: HH
authors: Kreipe
authors: Verena
authors: V
authors: Bröcker
authors: Jan Ulrich
authors: JU
authors: Becker
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000071120:ADAMTS13 Protein; D000328:Adult; D000368:Aged; D065095:Calcineurin Inhibitors; D005260:Female; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism*; D016030:Kidney Transplantation / Q000009:adverse effects*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000032:analysis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis*; D057049:Thrombotic Microangiopathies / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000032:analysis / Q000235:genetics
chemical_list: D065095:Calcineurin Inhibitors; C096161:KLF2 protein, human; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D010959:Tissue Plasminogen Activator; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human