Altered Glucose Metabolism and CCN

Altered metabolism of glucose, unique in diabetes as opposed to other forms of renal disease, is a critical factor contributing to increased CCN2 and DN. As described earlier, the exposure of a variety of renal cell types, including MCs, to elevated glucose levels has been shown to markedly increase CCN2 activity. This is likely to occur through at least two pathways in vivo. First, high glucose is able to increase protein kinase C, which

Fig. 2. Schematic diagram proposing a central role of CCN2 in the pathogenesis of diabetic nephropathy, and the interplay of contributing factors. (From ref. 52 with permission.)

then acts to upregulate TGF-P activity (16). As described earlier, TGF-P activity is well established as a major stimulatory factor for CCN2 production in a variety of renal and nonrenal cells. An increase in its activity is able to then increase CCN2, via a TGF-P responsive element on the CCN2 molecule (17).

A second pathway for glucose metabolism-driven CCN2 stimulation is via the generation of advanced glycation endproducts (AGE). These irreversibly formed biochemical endproducts of nonenzymatic glycosylation have been implicated as causal in the expansion of ECM that occurs in DN. AGE are present in the serum and in many tissues of diabetic patients. They have the ability to covalently crosslink and biochemically modify protein structure and function. AGE exposure upregulates, in a dose-dependent and dose-specific manner, CCN2 mRNA and protein level in dermal fibroblasts (18). In a similar manner, the exposure of cultured MCs to AGE increases both CCN2 and fibronectin expression (19). Further support for a role of AGE in this pathway has come from several in vivo studies using specific inhibitors of AGE formation (see the section on nonspecific inhibitors).

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