Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Keio University Health Center, 4-1-1 Hiyoshi, Kohoku-ku, Yokohama-shi, Kanagawa, 223-8521, Japan.
Sci Rep. 2022 Jun 29;12(1):10933. doi: 10.1038/s41598-022-15118-5.
There is a critical need for efficient treatment of chronic kidney disease (CKD). Renal fibrosis is a final common pathway to end-stage renal disease independent of the underlying etiology, and connective tissue growth factor (CTGF) is a well-recognized profibrotic factor in fibrosis of various organ systems. Here, we developed a novel peptide vaccine against CTGF to attenuate the development of renal fibrosis. Three inoculations with this CTGF vaccine at 2-week intervals elicited antibodies specifically binding to human full-length CTGF, and the antigen-specific serum IgG antibody titers were maintained for > 30 weeks. The efficacy of the CTGF vaccine on renal fibrosis was evaluated in adenine-induced CKD and unilateral ureteral obstruction (UUO) murine models. In adenine-induced CKD model, immunization with the CTGF vaccine attenuated renal interstitial fibrosis. Vaccinated mice showed low levels of serum creatinine and urea nitrogen and low urine albumin-creatinine ratio compared with vehicle-treated mice. In UUO model, the CTGF vaccination also suppressed the onset of renal fibrosis. In an in vitro study, CTGF vaccine-elicited IgG antibodies efficiently suppressed CTGF-induced- and transforming growth factor-β-induced α-smooth muscle actin expression in kidney fibroblasts. These results demonstrate that the CTGF vaccine is a promising strategy to attenuate the development of renal fibrosis.
治疗慢性肾脏病 (CKD) 需要高效的方法。肾纤维化是导致终末期肾病的共同途径，与潜在病因无关，而结缔组织生长因子 (CTGF) 是各种器官系统纤维化中公认的促纤维化因子。在这里，我们开发了一种针对 CTGF 的新型肽疫苗，以减轻肾纤维化的发展。用这种 CTGF 疫苗进行三次 2 周间隔的接种可引发特异性结合人全长 CTGF 的抗体，并且抗原特异性血清 IgG 抗体滴度可维持 30 周以上。在腺嘌呤诱导的 CKD 和单侧输尿管梗阻 (UUO) 小鼠模型中评估了 CTGF 疫苗对肾纤维化的疗效。在腺嘌呤诱导的 CKD 模型中，CTGF 疫苗接种可减轻肾间质纤维化。与对照组相比，接种疫苗的小鼠血清肌酐和尿素氮水平较低，尿白蛋白/肌酐比值也较低。在 UUO 模型中，CTGF 疫苗接种也抑制了肾纤维化的发生。在体外研究中，CTGF 疫苗诱导的 IgG 抗体可有效抑制 CTGF 诱导和转化生长因子-β诱导的肾成纤维细胞中α-平滑肌肌动蛋白的表达。这些结果表明 CTGF 疫苗是减轻肾纤维化发展的一种有前途的策略。
