Abstract:
Renal fibrosis is a representative pathological feature of various chronic kidney diseases, and efficient treatment is needed. Interstitial myofibroblasts are a key driver of kidney fibrosis, which is dependent on the binding of TGF-β1 to type I TGF-β receptor (TβRI) and TGF-β1-related signaling pathways. Therefore, attenuating TGF-β1 activity by competing with TGF-β1 in myofibroblasts is an ideal strategy for treating kidney fibrosis. Recently, a novel TβRI-mimicking peptide RIPΔ demonstrated a high affinity for TGF-β1. Thus, it could be speculated that RIPΔ may be used for anti-fibrosis therapy. Platelet-derived growth factor β receptor (PDGFβR) is highly expressed in fibrotic kidney. In this study, we found that target peptide Z-RIPΔ, which is RIPΔ modified with PDGFβR-specific affibody ZPDGFβR, was specifically and highly taken up by TGF-β1-activated NIH3T3 fibroblasts. Moreover, Z-RIPΔ effectively inhibited the myofibroblast proliferation, migration and fibrosis response in vitro. In vivo and ex vivo experiments showed that Z-RIPΔ specifically targeted fibrotic kidney, improved the damaged renal function, and ameliorated kidney histopathology and renal fibrosis in UUO mice. Mechanistic studies showed that Z-RIPΔ hold the stronger inhibition of the TGF-β1/Smad and TGF-β1/p38 pathways than unmodified RIPΔ in vitro and in vivo. Furthermore, systemic administration of Z-RIPΔ to UUO mice led to minimal toxicity to major organs. Taken together, RIPΔ modified with ZPDGFβR increased its therapeutic efficacy and reduced its systemic toxicity, making it a potential candidate for targeted therapy for kidney fibrosis.
摘要:
肾纤维化是各种慢性肾脏病的代表性病理特点,需要有效的治疗。间质肌成纤维细胞是肾纤维化的关键驱动因素,这取决于TGF-β1与I型TGF-β受体(TβRI)和TGF-β1相关信号通路的结合。因此,通过与肌成纤维细胞中的TGF-β1竞争来减弱TGF-β1活性是治疗肾纤维化的理想策略。最近,一种新的TβRI模拟肽RIPΔ表现出对TGF-β1的高亲和力。因此,可以推测RIPΔ可用于抗纤维化治疗。血小板衍生生长因子β受体(PDGFβR)在纤维化肾脏中高表达。在这项研究中,我们发现目标肽Z-RIPΔ,用PDGFβR特异性结合体ZPDGFβR修饰的RIPΔ,被TGF-β1激活的NIH3T3成纤维细胞特异性和高度吸收。此外,Z-RIPΔ有效抑制肌成纤维细胞增殖,体外迁移和纤维化反应。体内和离体实验表明,Z-RIPΔ特异性靶向纤维化肾,改善受损的肾功能,并改善UUO小鼠的肾脏组织病理学和肾脏纤维化。机制研究表明,在体外和体内,Z-RIPΔ比未修饰的RIPΔ对TGF-β1/Smad和TGF-β1/p38途径具有更强的抑制作用。此外,向UUO小鼠全身施用Z-RIPΔ导致对主要器官的最小毒性。一起来看,用ZPDGFβR修饰的RIPΔ增加了其治疗功效并降低了其全身毒性,使其成为肾脏纤维化靶向治疗的潜在候选者。