Biglycan, a Nitric Oxide-regulated Gene, Affects Adhesion, Growth, and Survival of Mesangial Cells

Abstract

During glomerular inflammation mesangial cells are the major source and target of nitric oxide that profoundly 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 timeand dose-dependently either by interleukin-1␤-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 upregulation 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-N 6 -(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.

Nitric oxide modulates expression of extracellular matrix genes linked to fibrosis in kidney mesangial cells

“…The observation that biglycan (BGN) is also a target of exogenous or endogenous NO in human MCs is consistent with studies by (Schaefer et al, 2003), who reported that BGN is an NO-regulated gene in rat MCs both in vitro and in vivo and that it is involved in the adhesion, proliferation and survival of MCs. Biglycan is a member of small, leucine-rich repeat glycoproteins/proteoglycans (SLRPs), which are thought to play a role as organizers of ECM (Hocking et al, 1998).…”

“…Overexpression of BGN is found in advanced stages of glomerulosclerosis (Davies, 1995). BGN is capable of inhibiting the proliferation of MCs induced by PDGF-B, a major mitogenic growth factor frequently involved in glomerular disease (Blom et al, 2001;Schaefer et al, 2003).…”

Renal Accumulation of Biglycan and Lipid Retention Accelerates Diabetic Nephropathy

“…21,22 The differences between our study and previous studies could simply be due to differences in the antibody affinity or to the examination of different stages of renal disease. In addition, the functional role or roles of biglycan are unclear; roles have been proposed in the maintenance of the glomerular charge barrier, 48,49 in the regulation of mesangial cell growth and survival, 50 in the regulation of TGF-␤ activity, 51 in the regulation of inflammation via activation of Toll-like receptors, 52 in the regulation of the assembly of connective tissues, 53 and in the structural composition of fibrosis, 22 among others. Both biglycan and decorin can bind TGF-␤, leading to its sequestration and neutralization of activity.…”

Small leucine-rich proteoglycans orchestrate receptor crosstalk during inflammation

“…43 Interaction of biglycan with other RTKs involved in decorin signaling has not been investigated up to now. Even though there is some evidence for the involvement of biglycan in inflammation, [44][45][46] only recently biglycan-mediated signal transduction has been described in macrophages. 14 Biglycan is abundant in the ECM of various organs.…”