N-acetyl-seryl-aspartyl-lysyl-proline prevents renal insufficiency and mesangial matrix expansion in diabetic db/db mice
N-acetyl-seryl-aspartyl-lysyl-proline prevents renal insufficiency and mesangial matrix expansion in diabetic db/db mice
复制标题
DOI：
10.2337/diabetes.54.3.838
复制
发表时间：
2005-03-01
期刊：
影响因子：
7.7
通讯作者：
Koya, D
中科院分区：
文献类型：
--
作者：
Shibuya, K;Kanasaki, K;Koya, D
我们先前报道，N-乙酰-丝氨酸-天冬氨酰-赖氨酰脯氨酸(Ac-SDKP)是一种经血管紧张素转换酶(ACE)降解的四肽，它通过抑制Smad信号通路抑制转化生长因子-β(TGF-β)诱导的人系膜细胞外基质蛋白的表达。为了在体内测试Ac-SDKP的抗纤维化效果，我们检测了Ac-SDKP长期治疗是否可以预防糖尿病db/db小鼠的肾功能不全和肾小球硬化。糖尿病db/db小鼠和非糖尿病db/m小鼠用Ac-SDKP用渗透压微泵治疗8周。Ac-SDKP治疗使两组患者的血浆Ac-SDKP浓度增加约三倍，但不影响血糖水平。组织学上，ac-SDKP显著抑制db/db小鼠肾小球表面积的增加、系膜基质的扩张和细胞外基质蛋白的过度产生。此外，Ac-SDKP治疗使db/db小鼠升高的血肌酸值正常化，而Ac-SDKP治疗db/db小鼠的蛋白尿与未治疗的db/db小鼠相比有所降低，尽管差异不具有统计学意义。Ac-SDKP可抑制Smad3的核转位。这些结果表明，Ac-SDKP可通过抑制转化生长因子-β/Smad途径改善db/db小鼠肾功能不全和肾小球硬化，提示Ac-SDKP可用于糖尿病肾病的治疗。
We have previously reported that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is a tetrapeptide hydrolyzed by ACE, inhibits the transforming growth factor-P (TGF-beta)-induced expression of extracellular matrix proteins via inhibition of the Smad signaling in human mesangial cells. To test in vivo the antifibrotic efficacy of Ac-SDKP, we examined whether long-term Ac-SDKP treatment can prevent renal insufficiency and glomerulosclerosis in diabetic db/db mice. Diabetic db/db mice or nondiabetic db/m mice were treated with Ac-SDKP for 8 weeks using osmotic minipumps. The treatment with Ac-SDKP increased plasma Ac-SDKP concentrations by approximately threefold in both groups but did not affect the blood glucose levels. Histologically, the increased glomerular surface area, mesangial matrix expansion, and overproduction of extracellular matrix proteins in db/db mice were significantly inhibited by Ac-SDKP. Furthermore, Ac-SDKP treatment normalized the increased plasma creatinine value in db/db mice, whereas the albuminuria in Ac-SDKP-treated db/db mice was somewhat decreased as compared with nontreated db/db mice, although the difference was not statistically significant. In addition, the nuclear translocation of Smad3 was inhibited by Ac-SDKP. These results demonstrate that long-term Ac-SDKP treatment ameliorates renal insufficiency and glomerulosclerosis in db/db mice via inhibition of TGF-beta/Smad pathway, suggesting that Ac-SDKP could be useful in the treatment of diabetic nephropathy.