title: Comprehensive analysis of glomerular mRNA expression of pro- and antithrombotic genes in atypical haemolytic-uremic syndrome (aHUS).
abstract: Atypical haemolytic-uremic syndrome (aHUS) is, in most cases, due to hereditary or acquired defects in complement regulation and a life-threatening disease. Despite the rapidly grown knowledge about the primary defects in aHUS, the pathogenesis that links complement dysregulation with microthrombus formation in aHUS is still unknown. Thus, we examined the glomerular microvascular expression of pro- and antithrombotic genes. Glomeruli were microdissected from 12 archival paraffin-embedded biopsies with aHUS and from seven control biopsies. Glomerular mRNA expression was quantified by single real-time PCR reactions after preamplification. In addition immunostains were performed for plasminogen activator inhibitor 1 (PAI-1) and for tissue plasminogen activator (tPA). Results were compared between cases and controls and with clinical data. Glomeruli in aHUS had increased mRNA expression of antifibrinolytic, prothrombotic PAI-1, antithrombotic thrombomodulin (THBD) and CD73 and decreased expression of profibrinolytic, antithrombotic tPA compared to controls. Impaired fibrinolysis due to increased microvascular expression of the antifibrinolytic PAI-1 in combination with the decreased expression of the profibrinolytic tPA seems to be a final common pathway in renal thrombotic microangiopathy that is also effective in aHUS. The concomitant induction of antithrombotic transcripts likely indicates counterregulatory efforts, demonstrating that the capillary bed is not a passive victim of complement attack. Future research should investigate if and how complement activation could induce the reported shift in the expression of PAI-1 and tPA.
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Modde
authors.forename: Putri Andina
authors.initials: PA
authors.lastname: Agustian
authors.forename: Juliane
authors.initials: J
authors.lastname: Wittig
authors.forename: Maximilian Ernst
authors.initials: ME
authors.lastname: Dämmrich
authors.forename: Vinzent
authors.initials: V
authors.lastname: Forstmeier
authors.forename: Udo
authors.initials: U
authors.lastname: Vester
authors.forename: Thurid
authors.initials: T
authors.lastname: Ahlenstiel
authors.forename: Kerstin
authors.initials: K
authors.lastname: Froede
authors.forename: Ulrich
authors.initials: U
authors.lastname: Budde
authors.forename: Anne-Margret
authors.initials: AM
authors.lastname: Wingen
authors.forename: Anke
authors.initials: A
authors.lastname: Schwarz
authors.forename: Svjetlana
authors.initials: S
authors.lastname: Lovric
authors.forename: Jan Thomas
authors.initials: JT
authors.lastname: Kielstein
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.forename: Nadine
authors.initials: N
authors.lastname: Bachmann
authors.forename: Mato
authors.initials: M
authors.lastname: Nagel
authors.forename: Hans Heinrich
authors.initials: HH
authors.lastname: Kreipe
authors.forename: Verena
authors.initials: V
authors.lastname: Bröcker
authors.forename: Clemens Luitpold
authors.initials: CL
authors.lastname: Bockmeyer
authors.forename: Jan Ulrich
authors.initials: JU
authors.lastname: Becker
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000071120:ADAMTS13 Protein; D000328:Adult; D065766:Atypical Hemolytic Uremic Syndrome; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis*; D010959:Tissue Plasminogen Activator / Q000032:analysis / Q000235:genetics*
chemical_list: C096161:KLF2 protein, human; 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