Effect of dsRNA on mesangial cell synthesis of plasminogen activator inhibitor type 1 and tissue plasminogen activator.
OBJECTIVE
Viral infections are a major problem worldwide and many of them are complicated by virally induced glomerulonephritides. Progression of kidney disease to renal failure is mainly attributed to the development of renal fibrosis characterized by the accumulation of extracellular matrix components in the mesangial cell compartment and the glomerular basement membrane. Plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA) are major regulators of plasmin generation and play an important role in generation and degradation of glomerular extracellular matrix components. Viral receptors expressed by mesangial cells (MC) are known to be key mediators in immune-mediated glomerulonephritis. We investigated the effect of stimulation of the viral receptors toll-like receptor 3 (TLR3) and retinoic acid-inducible gene I (RIG-I) on the expression of PAI-1 and t-PA.


METHODS
Expression of PAI-1 and t-PA in immortalized human MC stimulated with polyriboinosinic:polyribocytidylic acid [poly(I:C)] RNA and cytokines were analyzed by real-time RT-PCR and ELISA.


RESULTS
Incubation of MC with poly(I:C) RNA to activate the viral receptors TLR3 and RIG-I upregulates the expression of PAI-1 and t-PA. Knockdown of viral receptors with specific siRNA abolishes the induction of PAI-1 and t-PA.


CONCLUSIONS
For the first time a link between the activation of viral receptors on MC and potentially causative agents in the development of glomerulosclerosis and tubulointerstitial fibrosis is shown. The progression of inflammatory processes to glomerulosclerosis can be postulated to be directly enhanced by viral infection.
Wörnle
Markus
M
Medical Policlinic, Ludwig Maximilians University, Munich, Germany. Markus.Woernle@med.uni-muenchen.de
Roeder
Maximilian
M
Sauter
Matthias
M
Merkle
Monika
M
Ribeiro
Andrea
A
D002478:Cells, Cultured; D006801:Humans; D050527:Mesangial Cells / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D012330:RNA, Double-Stranded / Q000502:physiology*; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis*
D017395:Plasminogen Activator Inhibitor 1; D012330:RNA, Double-Stranded; D010959:Tissue Plasminogen Activator