Biglycan, a nitric oxide-regulated gene, affects adhesion, growth, and survival of mesangial cells.
During glomerular inflammation mesangial cells are the major source and target of nitric oxide that pro-foundly influences proliferation, adhesion, and death of mesangial cells. The effect of nitric oxide on the mRNA expression pattern of cultured rat mesangial cells was therefore investigated by RNA-arbitrarily-primed polymerase chain reaction. Employing this approach, biglycan expression turned out to be down-regulated time- and dose-dependently either by interleukin-1beta-stimulated endogenous nitric oxide production or by direct application of the exogenous nitric oxide donor, diethylenetriamine nitric oxide. There was a corresponding decline in the rate of biglycan biosynthesis and in the steady state level of this proteoglycan. In vivo, in a model of mesangioproliferative glomerulonephritis up-regulation of inducible nitric-oxide synthase mRNA was associated with reduced expression of biglycan in isolated glomeruli. Biglycan expression could be normalized, both in vitro and in vivo, by using a specific inhibitor of the inducible nitric-oxide synthase, l-N6-(l-iminoethyl)-l-lysine dihydrochloride. Further studies showed that biglycan inhibited cell adhesion on type I collagen and fibronectin because of its binding to these substrates. More importantly, biglycan protected mesangial cells from apoptosis by decreasing caspase-3 activity, and it counteracted the proliferative effects of platelet-derived growth factor-BB. These findings indicate a signaling role of biglycan and describe a novel pathomechanism by which nitric oxide modulates the course of renal glomerular disease through regulation of biglycan expression.
Department of Medicine D, Albert-Schweitzer-Str. 33, University of Münster, 48149 Münster, Germany. schaefl@unimuenster.de
Liliana
L
Schaefer
Karl-Friedrich
KF
Beck
Igor
I
Raslik
Sebastian
S
Walpen
Daniel
D
Mihalik
Miroslava
M
Micegova
Katarina
K
Macakova
Elke
E
Schonherr
Daniela G
DG
Seidler
Georg
G
Varga
Roland M
RM
Schaefer
Hans
H
Kresse
Josef
J
Pfeilschifter
D000818:Animals; D000077214:Becaplermin; D058578:Biglycan; D015152:Blotting, Northern; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion; D002455:Cell Division; D002460:Cell Line; D002469:Cell Separation; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins; D005434:Flow Cytometry; D005920:Glomerular Mesangium / Q000378:metabolism*; D005921:Glomerulonephritis / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007375:Interleukin-1 / Q000378:metabolism; D009336:Necrosis; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011509:Proteoglycans / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D015854:Up-Regulation
C546884:BGN protein, human; C546886:Bgn protein, rat; D058578:Biglycan; D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; D010982:Platelet-Derived Growth Factor; D011509:Proteoglycans; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D000077214:Becaplermin; D009569:Nitric Oxide; D012313:RNA; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases