gms | German Medical Science

In glomerular hypertension, glomerular mesangial cells (MC) activated by pressure are central to pathogenesis of progressive glomeruli-associated renal diseases due to their proliferation and inflammatory mediator release. Urokinase-type plasminogen activator (uPA) and its specific receptor (uPAR) are multifunctional molecules involved in pericellular, fibrinolytic and proteolytic activities, as well as in cell adhesion, migration and proliferation, most likely by affecting intracellular signalling. Under normal condition, glomerular expression of the uPA/uPAR system components is very low, whereas in pathological situations accompanied by glomerular hypertension MC express uPA, uPAR and plasminogen activator inhibitors (PAI-1/2). However, molecular mechanisms utilized by the uPA/uPAR system in MC underlying changes in MC functions still remain poorly understood.

Now we show that uPA via uPAR contributes significantly to the regulation of normal human MC proliferation. Moreover, uPA/uPAR induce in MC upregulated expression of the complement anaphylatoxin C5a receptor (C5aR, CD88) and modulates C5a-dependent functional response. The Janus kinase Tyk2 and transcription factor Stat3 serve as downstream components in the signaling cascade resulting in the upregulated C5aR expression. In vivo, expression of C5aR and uPAR was increased in mesangial tissue of wild type mice in a lypopolysaccharide (LPS)-induced model of inflammation, whereas in uPAR-/- animals C5aR expression was reduced. This is the first demonstration in vitro and in vivo that uPA acts in MC as a modulator of immune responses via control of immune competent receptors. The data suggest a novel role for the uPA/uPAR in glomeruli-associated renal failure via signaling cross-talk between the fibrinolytic and immune systems.