Proteomic approach to protein involving diabetic nephropathy

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In diabetic renal disease or non-diabetic renal disease, TGF-beat plays a role in the disease progression. Identification of the protein interacting TGF-beta or its down-stream molecule such as Smad is the strategy to investigate the novel protein involving the progressive diabetic or non-diabetic nephropathy. The renin-angiotensin system(RAS)and the accumulation of advanced glycation end products(AGEs)have been implicated in the pathogenesis of diabetic nephropathy. we investigated whether AGEs could activate autocrine angiotensin II(Ang II)signaling and subsequently induce transforming growth factor-beta(TGF-beta)-Smad signaling in cultured rat mesangial cells. AGEs increased intracellular ROS generation in mesangial cells, and this effect was significantly inhibited by an antiserum against RAGE. AGEs also were found to stimulate Ang II production in a time- and dose-dependent manner, which was completely prevented by an antioxidant, N-acetylcysteine(NAC). AGE-induced TGF-beta overproduction was blocked by candesartan, an Ang II type 1 receptor(AT1R)antagonist. Both candesartan and neutralizing antibody against TGF-beta prevented AGEs-induced Smad2 phosphorylation and TGF-beta-inducible promoter activity. AGEs were found to inhibit DNA synthesis and to stimulate de novo protein synthesis and fibronectin production in association with up-regulation of p27. All of these phenomena were prevented by candesartan or a polyclonal antibody against TGF-beta. AGE-RAGE-mediated ROS generation activates TGF-beta-Smad signaling and subsequently induces mesangial cell hypertrophy and fibronectin synthesis by autocrine production of Ang II. Thus, the AGE, Ang II, and TGF-b-Smad interact tightly in diabetic nephropathy. Base upon these result, we are going to investigate the protein involving diabetic nephropathy.