Effect of dsRNA on Mesangial Cell Synthesis of Plasminogen Activator Inhibitor Type 1 and Tissue Plasminogen Activator

Background/Aims: 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. Conclusion: 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. Copyright (C) 2009 S. Karger AG, Basel