siRNAgen Therapeutics, Daejeon 34302, Republic of Korea.
Bioneer Corporation, Daejeon 34302, Republic of Korea.
Radiat Res. 2022 May 1;197(5):471-479. doi: 10.1667/RADE-21-00220.1.
Fibrosis is a serious unintended side effect of radiation therapy. In this study, we aimed to investigate whether amphiregulin (AREG) plays a critical role in fibrosis development after total-body irradiation (TBI). We found that the expression of AREG and fibrotic markers, such as α-smooth muscle actin (α-SMA) and collagen type I alpha 1 (COL1α1), was elevated in the kidneys of 6 Gy TBI mice. Expression of AREG and α-SMA was mainly elevated in the proximal and distal tubules of the kidney in response to TBI, which was confirmed by immunofluorescence staining. Knockdown of Areg mRNA using self-assembled-micelle inhibitory RNA (SAMiRNA) significantly reduced the expression of fibrotic markers, including α-SMA and COL1α1, and inflammatory regulators. Finally, intravenous injections of SAMiRNA targeting mouse Areg mRNA (SAMiRNA-mAREG) diminished radiation-induced collagen accumulation in the renal cortex and medulla. Taken together, the results of the present study suggest that blocking of AREG signaling via SAMiRNA-mAREG treatment could be a promising therapeutic approach to alleviate radiation-induced kidney fibrosis.
纤维化是放射治疗的一种严重的非预期副作用。在这项研究中，我们旨在研究表皮调节素 (AREG) 是否在全身照射 (TBI) 后纤维化发展中起关键作用。我们发现，6 Gy TBI 小鼠的肾脏中 AREG 和纤维化标志物（如α-平滑肌肌动蛋白 (α-SMA) 和 I 型胶原α 1 (COL1α1)）的表达升高。免疫荧光染色证实，AREG 和 α-SMA 的表达主要在肾脏的近端和远端小管中因 TBI 而升高。使用自组装胶束抑制 RNA (SAMiRNA) 敲低 Areg mRNA 显著降低了纤维化标志物（包括α-SMA 和 COL1α1）和炎症调节剂的表达。最后，靶向小鼠 Areg mRNA 的 SAMiRNA（SAMiRNA-mAREG）的静脉内注射减少了肾皮质和髓质中辐射诱导的胶原蛋白积累。总之，本研究结果表明，通过 SAMiRNA-mAREG 治疗阻断 AREG 信号可能是一种有前途的治疗方法，可减轻辐射诱导的肾脏纤维化。
