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Glycosaminoglycan Therapy Prevents TGF-ß1 Overexpression and Pathologic Changes in Renal Tissue of Long-Term Diabetic Rats

MONICA CEOL^*,, GIOVANNI GAMBARO^*, ULRICH SAUER, BRUNO BAGGIO^*, FRANCA ANGLANI^*, MONICA FORINO^*, SONIA FACCHIN^*,, LUCIANA BORDIN^§, CORA WEIGERT, ANDREAS NERLICH and ERWIN D. SCHLEICHER

^* Institute of Internal Medicine, Division of Nephrology, University of Padova, Padova, Italy
^§ Department of Biochemistry, University of Padova, Padova, Italy
Department of Internal Medicine, Division of Endocrinology, Metabolism, and Pathobiochemistry, University of Tübingen, Tübingen, Germany
Institute of Pathology, University of Munich, Munich, Germany.

Correspondence to Dr. Erwin D. Schleicher, Department of Internal Medicine, Division of Endocrinology, Metabolism, and Pathobiochemistry, Eberhard-Karls-Universität, Otfried-Müller-Straße 10, D-72076, Tübingen, Germany. Phone: 49-7071-29-87599; Fax: 49-7071-29-5974; E-mail: enschlei{at}med.uni-tuebingen.de

Abstract. Chronic induction of the prosclerotic cytokine transforming growth factor ß (TGF-ß) has been implicated in the pathogenesis of diabetic nephropathy. In a rat model of diabetes mellitus-induced glomerulosclerosis, daily administration of a modified heparin (mH) glycosaminoglycan (GAG) preparation with low anticoagulant activity prevented glomerular and tubular matrix accumulation, as well as overexpression of TGF-ß1 mRNA and albuminuria, without obvious side effects. To elucidate the molecular mechanisms of GAG/mH inhibitory actions on TGF-ß1, studies using cultured mesangial cells were also performed. In these cells, high glucose-induced, dose-dependent increases in TGF-ß1 mRNA and bioactive TGF-ß protein expression were inhibited by GAG/mH treatment, whereas basal TGF-ß1 expression was not affected. Both the heparin-derived GAG and dermatan sulfate were effective, indicating that the heparin chemical structure is not necessary for inhibitory activity. Coincubation of GAG with active TGF-ß1 demonstrated no inhibitory effect on TGF-ß1 bioactivity, excluding a neutralizing effect of GAG on TGF-ß1 at the protein level. Furthermore, it was demonstrated that GAG inhibited phorbol myristate acetate-induced translocation of protein kinase C- (PKC-) and -ß1 and activation of PKC-, as well as high glucose-induced activation of PKC-. These results suggest that GAG inhibit TGF-ß1 overexpression at the transcriptional level, possibly via inhibition of high glucose-activated PKC. The findings indicate the potential of GAG therapy for the prevention of diabetic glomerulosclerosis by the inhibition of chronic disease-induced TGF-ß1 mRNA overexpression.

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