Department of General Surgery, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China.
Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, USA.
Clin Exp Pharmacol Physiol. 2023 Sep;50(9):711-718. doi: 10.1111/1440-1681.13768. Epub 2023 Jun 13.
The prognosis of multiple myeloma (MM) patients combined with renal insufficiency is poor. Renal fibrosis is an important pathological cause for MM patients combined with renal insufficiency. It is reported that epithelial-mesenchymal transition (EMT) of renal proximal tubular epithelial cells is an important mechanism in renal fibrosis. We speculated that EMT might play an important role in the renal insufficiency of MM with unclear mechanism. MM cells derived exosomes could affect the function of targeted cells by delivering microRNAs (miRNAs). Literature has shown that the expression of miR-21 is closely related to EMT. In this research, we found that co-culture of HK-2 cells (human renal proximal tubular epithelial cells) and exosomes derived from MM cells promoted the EMT of HK-2 cells, resulting in the down-regulation of epithelial-related marker (E-cadherin), and up-regulation of stroma-related marker (Vimentin). Meanwhile, the expression of SMAD7, one of the downstream targets in the TGF-β signalling pathway, was suppressed and the expression of TGF-β was increased. After transfecting the inhibitor of miR-21 in MM cells, the expression of miR-21 in exosomes secreted by MM cells was significantly decreased, and the co-culture of these treated exosomes and HK-2 cells inhibited the EMT of HK-2 cells. In conclusion, these findings showed that exosomal miR-21 derived from MM cells could promote renal EMT through targeting TGF-β/SMAD7 signalling pathway.
多发性骨髓瘤（MM）合并肾功能不全患者的预后较差。肾纤维化是 MM 合并肾功能不全的重要病理原因。有报道称，肾近端小管上皮细胞的上皮-间充质转化（EMT）是肾纤维化的重要机制之一。我们推测 EMT 可能在 MM 合并肾功能不全的发病机制中起重要作用，但具体机制尚不清楚。MM 细胞衍生的外泌体可以通过传递 microRNAs（miRNAs）来影响靶细胞的功能。文献表明，miR-21 的表达与 EMT 密切相关。在本研究中，我们发现 HK-2 细胞（人肾近端小管上皮细胞）与 MM 细胞衍生的外泌体共培养可促进 HK-2 细胞的 EMT，导致上皮相关标志物（E-钙黏蛋白）下调，间质相关标志物（波形蛋白）上调。同时，TGF-β 信号通路下游靶标 SMAD7 的表达受到抑制，TGF-β 的表达增加。在 MM 细胞中转染 miR-21 抑制剂后，MM 细胞分泌的外泌体中的 miR-21 表达明显降低，这些经处理的外泌体与 HK-2 细胞共培养可抑制 HK-2 细胞的 EMT。总之，这些发现表明 MM 细胞来源的外泌体 miR-21 可通过靶向 TGF-β/SMAD7 信号通路促进肾 EMT。
