Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Sci Rep. 2017 Oct 12;7(1):13086. doi: 10.1038/s41598-017-13486-x.
Kidney fibrosis and fibrogenesis significantly exacerbate chronic kidney disease (CKD) progression and are essential therapeutic targets. Bortezomib (BZM) is a proteasome inhibitor used for the treatment of multiple myeloma (MM). Several studies have demonstrated that BZM attenuates renal impairment in patients with MM, although this effect is generally considered to be the result of MM remission. Recently, several studies on BZM reported anti-fibrotic effects on liver and skin in experimental animal models. However, its effect on renal fibrosis has yet to be examined. Here, we investigated the anti-fibrotic effects of BZM in an experimental mouse model of fibrosis that uses aristolochic acid I (AA). Ten weeks of AA administration with BZM treatment twice a week significantly attenuated AA-induced renal dysfunction and albuminuria, reduced the expression of renal fibrosis-related proteins and kidney injury markers, such as αSMA, Kim1, and Ngal, and prevented renal fibrosis at the level of histopathology. Furthermore, pathological activation of TGFβ1-Smad3 signaling and apoptosis, essential pathophysiological causes of AA-induced nephropathy (AAN), were ameliorated by BZM, suggesting this mechanism may be involved in improving fibrosis in AAN. In conclusion, BZM directly inhibits renal fibrosis in CKD via suppression of TGFβ1-Smad3 signaling and is promising in terms of drug repositioning.
肾纤维化和纤维发生显著加剧慢性肾脏病（CKD）的进展，是重要的治疗靶点。硼替佐米（BZM）是一种蛋白酶体抑制剂，用于治疗多发性骨髓瘤（MM）。几项研究表明，BZM 可减轻 MM 患者的肾功能损害，尽管这种作用通常被认为是 MM 缓解的结果。最近，几项关于 BZM 的研究报告称，其在实验动物模型中对肝和皮肤具有抗纤维化作用。然而，其对肾纤维化的作用尚未得到检验。在这里，我们研究了 BZM 在使用马兜铃酸 I（AA）的纤维化实验小鼠模型中的抗纤维化作用。每周两次用 BZM 治疗 10 周可显著减轻 AA 诱导的肾功能障碍和蛋白尿，减少肾脏纤维化相关蛋白和肾损伤标志物（如 αSMA、Kim1 和 Ngal）的表达，并可预防组织病理学水平的肾纤维化。此外，BZM 可改善 TGFβ1-Smad3 信号通路和细胞凋亡的病理性激活，这是 AA 诱导的肾病（AAN）的重要病理生理原因，表明该机制可能参与改善 AAN 的纤维化。总之，BZM 通过抑制 TGFβ1-Smad3 信号通路直接抑制 CKD 中的肾纤维化，在药物再定位方面具有广阔的前景。
