Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy
Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy
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DOI：
10.1074/jbc.m310428200
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发表时间：
2004-05-07
影响因子：
4.8
通讯作者：
Doi, T
中科院分区：
文献类型：
--
作者：
Ohashi, S;Abe, H;Doi, T
晚期糖基化终产物（AGE）似乎会导致糖尿病并发症。本研究报告了 AGE 形成抑制剂 OPB-9195 (OPB) 的抑制作用，以及胶原蛋白特异性分子伴侣、47 kDa 热休克蛋白 (HSP47) 在糖尿病肾病中的作用。携带与胰岛素启动子融合的一氧化氮合酶 cDNA (iNOSTg) 的转基因小鼠会导致糖尿病。 6月龄的iNOSTg小鼠表现出弥漫性肾小球硬化，系膜区HSP47的表达显着增加，同时I型和IV型胶原蛋白的表达增加。 OPB 治疗改善了 iNOSTg 小鼠的肾小球硬化，这与 HSP47 以及 I 型和 IV 型胶原蛋白表达减少有关。 iNOSTg 小鼠肾小球中转化生长因子-β (TGF-β) 的表达增加，而 OPB 治疗后表达减少。为了证实这些机制，用 AGE 刺激培养的系膜细胞。 AGE 显着增加 HSP47、IV 型胶原和 TGF-β mRNA 的表达。 TGF-β 的中和抗体在体外抑制 HSP47 和 IV 型胶原的过度表达。总之，无论在体内还是体外，AGEs 都会增加与胶原蛋白相关的 HSP47 的表达。该过程可能由 TGF-β 介导。
Advanced glycation end products (AGEs) appear to contribute to the diabetic complications. This study reports the inhibitory effect of OPB-9195 (OPB), an inhibitor of AGEs formation, and the role of a collagen-specific molecular chaperone, a 47-kDa heat shock protein (HSP47) in diabetic nephropathy. Transgenic mice carrying nitric-oxide synthase cDNA fused with insulin promoter (iNOSTg) leads to diabetes mellitus. The iNOSTg mice at 6 months of age represented diffuse glomerulosclerosis, and the expression of HSP47 was markedly increased in the mesangial area in parallel with increased expression of types I and IV collagens. OPB treatment ameliorated glomerulosclerosis in the iNOSTg mice associated with the decreased expression of HSP47 and types I and IV collagens. The expression of transforming growth factor-beta (TGF-beta) was increased in glomeruli of iNOSTg mice and decreased after treatment with OPB. To confirm these mechanisms, cultured mesangial cells were stimulated with AGEs. AGEs significantly increased the expression of HSP47, type IV collagen, and TGF-beta mRNA. Neutralizing antibody for TGF-beta inhibited the overexpression of both HSP47 and type IV collagen in vitro. In conclusion, AGEs increase the expression of HSP47 in association with collagens, both in vivo and in vitro. The processes may be mediated by TGF-beta.