Besides the inhibitory Smads, the receptor-regulated Smads (R-Smads) that can transduce a TGF-P signal are Smad2 and Smad3. In particular, Smad3 may be involved in the stimulatory effect of high glucose on ECM expression. In mouse MCs, high glucose stimulates the transcription of fibronectin and potentiates the transcriptional activation of fibronectin by TGF-P1 (168). This effect of TGF-P1 appears to be mediated by Smad3, because overexpression of Smad3 was able to induce fibronectin promoter activity by itself. Smad3 overexpression also increased fibronectin synergistically in conjunction with exogenous TGF-P1, as if the extra Smad3 had increased the efficiency of TGF-P signaling. More importantly, transfection of a Smad3-dominant-negative construct was able to inhibit TGF-P 1 from stimulating the promoter activity of fibronectin (168). However, part of the TGF-P 1-induced fibronectin expression may also be mediated in parallel by the p38 mitogen-activated protein kinase (MAPK) pathway (136). Finally, there is evidence to suggest that Smad3 predominantly mediates the effect of TGF-P1 to increase the mRNA expression of a1(I) collagen (136).

Little information is available, however, regarding Smad2 as a therapeutic target in DN. However, Smad2 has been shown to be increased in protein expression and to be activated in the kidney of the Otsuka Long-Evans Tokushima Fatty rat, a model of spontaneous type-2 diabetes (180). In the model of type 1 diabetes induced by STZ, Smad2 signaling was also activated in the glomerular cells, evidenced by immunostain-ing for phosphorylated Smad2 (181).

In contrast, blockade of Smad3 as a therapeutic tool in diabetic kidney disease is becoming feasible in vivo. In one study, Smad3-null mice, created on a CL57/Bl6J strain background, were made diabetic by STZ (182). After 4 wk of diabetes, glomerular expression of TGF-P1, as assessed by RTPCR, was not enhanced in Smad3-null mice vs wild-type, indicating that the absence of Smad3 did not result in a compensatory increase of the TGF-P message. Matrix expression was inhibited, however, in the kidneys of the Smad3-null mice; mRNA levels of fibronectin and the a3 chain of type IV collagen were increased in the diabetic wild-type mice (compared with the nondiabetic controls), but not in the diabetic Smad3-null mice (182). Along with the increase in a3(IV) collagen in diabetes, glomerular basement membrane thickening had occurred in the wild-type mice but was significantly prevented in the diabetic Smad3-null mice. Thus, Smad3 seems to function in the diabetes-induced upregulation of fibronectin and a3(IV) collagen, and thereby may play a critical role in the early phase of diabetic glomerulopathy (182).

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