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J. Biol. Chem., Vol. 278, Issue 28, 26227-26237, July 11, 2003

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

Liliana Schaefer  , Karl-Friedrich Beck ¶, Igor Raslik ||, Sebastian Walpen ¶, Daniel Mihalik , Miroslava Micegova , Katarina Macakova , Elke Schönherr **, Daniela G. Seidler **, Georg Varga , Roland M. Schaefer , Hans Kresse ** and Josef Pfeilschifter ¶

From the Departments of Medicine D, Albert-Schweitzer-Str. 33, ^**Physiological Chemistry and Pathobiochemistry, Waldeyerstr. 15, and Dermatology, Von-Esmarchstr. 58, University of Münster, 48149 Münster, Germany, ^¶Pharmazentrum Frankfurt, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany, and ^||Institute of Molecular Biology, Slovak Academy of Sciences, Dubravska cesta 21, 84251 Bratislava, Slovak Republic

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-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 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.

Received for publication, October 16, 2002 , and in revised form, March 24, 2003.

^* This work was supported by the Deutsche Forschungsgemeinschaft (SFB 492, project B10 and SFB 553, projects SCHA 970/1–1 and PF 361/1–1) and the Interdisciplinary Centre for Clinical Research, University of Münster (Project D18). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Medizinische Klinik und Poliklinik D, Albert-Schweitzer-Str. 33, 48149 Münster, Germany. Tel.: 49-251-834-7525; Fax: 49-251-834-9547; E-mail: schaefl{at}unimuenster.de.

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