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Renal Connective Tissue Growth Factor Induction in Experimental Diabetes Is Prevented by Aminoguanidine

Kolling Institute of Medical Research (S.M.T.), University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia; Department of Diabetic Complications (Z.C., W.C.B., G.B., J.M.F., M.E.C.), Baker Medical Research Institute, Melbourne, Victoria 3004, Australia; and Department of Medicine (S.V.M.), University of Sydney, Sydney 2006, Australia

Address all correspondence and requests for reprints to: Prof. Mark Cooper, Department of Diabetic Complications, Baker Medical Research Institute, Commercial Road, Melbourne, Victoria 3004, Australia. E-mail: mark.cooper{at}baker.edu.au.

The aim of this study was to determine whether aminoguanidine (AG), an inhibitor of advanced glycation, prevents expression of the profibrotic cytokine, connective tissue growth factor (CTGF), as well as accumulation of the previously reported CTGF-dependent matrix protein, fibronectin, in a model of experimental diabetic nephropathy. Diabetic animals were randomly allocated into groups receiving 32 wk of AG or vehicle. Diabetic rats showed increases in CTGF mRNA and protein expression as well as in advanced glycation end-product (AGE) and fibronectin immunostaining, compared with nondiabetic rats. In the diabetic kidney, the increase in CTGF gene and protein expression as well as expression of the extracellular matrix protein fibronectin were prevented by AG. To further explore the relationship between AGEs and mesangial CTGF and fibronectin production, cultured human mesangial cells were exposed in vitro to soluble AGE-BSA and carboxymethyl lysine-BSA, and this led to induction of both CTGF and fibronectin. On the basis of our in vitro findings in mesangial cells linking AGEs to CTGF expression, the known prosclerotic effects of CTGF, and the ability of AG to attenuate mesangial expansion, it is postulated that the antifibrotic effects of AG in this animal model may be partially mediated by CTGF.

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