Effect of N-acetyl seryl-aspartyl-lysyl-proline on renal insufficiency and mesangial matrix expansion in diabetic db/db mice

我们首次发现由ACE水解的四肽n -乙酰-seryl-aspartyl-lysyl-脯氨酸（Ac-SDKP）通过抑制人系膜细胞Smad信号传导抑制tgf - β诱导的细胞外基质蛋白的表达。接下来，为了在体内测试Ac-SDKP的抗纤维化功效，我们研究了长期Ac-SDKP治疗是否可以预防糖尿病db/db小鼠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小鼠经渗透微型泵灌胃Ac-SDKP 8周。在两组中，Ac-SDKP治疗使血浆Ac-SDKP浓度增加了约三倍，但对血糖水平没有影响。组织学上，Ac-SDKP显著抑制db/db小鼠肾小球表面积增加、系膜基质扩张和细胞外基质蛋白过量产生。此外，Ac-SDKP治疗使db/db小鼠的血浆肌酐值升高正常化，而Ac-SDKP治疗的db/db小鼠的蛋白尿与未治疗的db/db小鼠相比有所下降，尽管差异无统计学意义。此外，Ac-SDKP抑制Smad3的核易位。这些结果表明，Ac-SDKP长期治疗可通过抑制tgf - β /Smad通路改善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 firstly found that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is a tetrapeptide hydrolyzed by ACE, inhibits the transforming growth factor-beta(TGF-beta)-induced expression of extracellular matrix proteins via inhibition of the Smad signaling in human mesangial cells. Next, 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.