Yang Cheng, Cao Ye, Zhang Yi, Li Long, Xu Ming, Long Yaqiu, Rong Ruiming, Zhu Tongyu
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Shanghai Key Laboratory of Organ Transplantation, 180 Fenglin Road, Shanghai, 200032, China.
J Transl Med. 2015 Nov 10;13:355. doi: 10.1186/s12967-015-0699-2.
Renal fibrosis is a main cause of end-stage renal disease. Clinically, there is no beneficial treatment that can effectively reverse the progressive loss of renal function. We recently synthesized a novel proteolysis-resistant cyclic helix B peptide (CHBP) that exhibits promising renoprotective effects. In this study, we evaluated the effect of CHBP on renal fibrosis in an in vivo ischemia reperfusion injury (IRI) model and in vitro TGF-β-stimulated tubular epithelial cells (TCMK-1 and HK-2) model. In the IRI in vivo model, mice were randomly divided into sham (sham operation), IR and IR + CHBP groups (n = 6). CHBP (8 nmol/kg) was administered intraperitoneally at the onset of reperfusion, and renal fibrosis was evaluated at 12 weeks post-reperfusion. Our results showed that CHBP markedly attenuated the IRI-induced deposition of collagen I and vimentin. In the in vitro model, CHBP reversed the TGF-β-induced down-regulation of E-cadherin and up-regulation of α-SMA and vimentin. Furthermore, CHBP inhibited the phosphorylation of Akt and Forkhead box O 3a (FoxO3a), whose anti-fibrotic effect could be reversed by the 3-phosphoinositide-dependent kinase-1 (PI3K) inhibitor wortmannin as well as FoxO3a siRNA. These findings demonstrate that CHBP attenuates renal fibrosis and the epithelial-mesenchymal transition of tubular cells, possibly through suppression of the PI3K/Akt pathway and thereby the inhibition FoxO3a activity.
肾纤维化是终末期肾病的主要原因。临床上，尚无有效的治疗方法能够有效逆转肾功能的进行性丧失。我们最近合成了一种新型的抗蛋白水解环螺旋B肽（CHBP），其显示出有前景的肾脏保护作用。在本研究中，我们在体内缺血再灌注损伤（IRI）模型和体外转化生长因子-β（TGF-β）刺激的肾小管上皮细胞（TCMK-1和HK-2）模型中评估了CHBP对肾纤维化的影响。在体内IRI模型中，将小鼠随机分为假手术（假手术操作）、IR和IR + CHBP组（n = 6）。在再灌注开始时腹腔注射CHBP（8 nmol/kg），并在再灌注后12周评估肾纤维化。我们的结果表明，CHBP显著减轻了IRI诱导的I型胶原蛋白和波形蛋白的沉积。在体外模型中，CHBP逆转了TGF-β诱导的E-钙黏蛋白下调以及α-平滑肌肌动蛋白（α-SMA）和波形蛋白的上调。此外，CHBP抑制了Akt和叉头框O 3a（FoxO3a）的磷酸化，其抗纤维化作用可被3-磷酸肌醇依赖性激酶-1（PI3K）抑制剂渥曼青霉素以及FoxO3a小干扰RNA（siRNA）逆转。这些发现表明，CHBP可能通过抑制PI3K/Akt途径从而抑制FoxO3a活性来减轻肾纤维化和肾小管细胞的上皮-间质转化。
