Exogenous nitric oxide inhibits mesangial cell adhesion to extracellular matrix components.
Interactions of mesangial cells (MCs) with components of the extracellular matrix (ECM) profoundly influence the MC phenotype, such as attachment, contraction, migration, survival and proliferation. Here, we investigated the effects of exogenous nitric oxide (NO) on the process of MC adhesion to ECM molecules. Incubation of rat MCs with the NO donor S-nitroso-N-acetylpenicillamine (SNAP) dose- and time-dependently inhibited MC adhesion and spreading on various ECM substrata, being more pronounced on collagen type I than on collagen type IV, laminin or fibronectin. In contrast, SNAP did not inhibit MC adhesion to L-polylysine-coated plates. The inhibitory effects of SNAP were reduced by hemoglobin and enhanced by superoxide dismutase. The anti-adhesive action of SNAP was mimicked not only by other NO donors but also by 8-bromo-cGMP, and significantly reversed by the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-alpha]quinoxalin-1-one (ODQ). Moreover, SNAP and 8-bromo-cGMP decreased the adhesion-induced phosphorylation of focal adhesion kinase (pp125FAK). In the presence of SNAP or 8-bromo-cGMP, adherent MCs exhibited disturbed organization of alpha-actin filaments and reduced numbers of focal adhesions, as shown by immunocytochemistry. In additional experiments with adherent MCs, it was found that exposure to SNAP or 8-bromo-cGMP for 12 and 24 hours induced detachment of MCs. The results indicate that exogenous NO interferes with the establishment and maintenance of MC adhesion to ECM components. This inhibitory NO effect is mediated predominantly by cGMP-signaling. Disturbance of MC attachment to ECM molecules could represent an important mechanism by which NO affects MC behavior in vitro and in vivo.
Yao
J
J
Medizinische Klinik IV, Universität Erlangen-Nürnberg, Germany.
Schoecklmann
H O
HO
Pröls
F
F
Gauer
S
S
Sterzel
R B
RB
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D026423:S-Nitroso-N-Acetylpenicillamine; D026422:S-Nitrosoglutathione; D015398:Signal Transduction
D015815:Cell Adhesion Molecules; D009603:Nitroso Compounds; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; C002385:linsidomine; D026423:S-Nitroso-N-Acetylpenicillamine; D003094:Collagen; D008981:Molsidomine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496052:Ptk2 protein, rat; D005978:Glutathione; D010396:Penicillamine; D006152:Cyclic GMP