In vivo silencing of amphiregulin by a novel effective Self-Assembled-Micelle inhibitory RNA ameliorates renal fibrosis via inhibition of EGFR signalsopen access
- Authors
- Son, Seung Seob; Hwang, Soohyun; Park, Jun Hong; Ko, Youngho; Yun, Sung-Il; Lee, Ji-Hye; Son, Beomseok; Kim, Tae Rim; Park, Han-Oh; Lee, Eun Young
- Issue Date
- 26-Jan-2021
- Publisher
- Nature Publishing Group
- Keywords
- 의약학
- Citation
- Scientific Reports, v.11, no.1
- Journal Title
- Scientific Reports
- Volume
- 11
- Number
- 1
- URI
- https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/1934
- DOI
- 10.1038/s41598-021-81726-2
- ISSN
- 2045-2322
- Abstract
- Amphiregulin (AREG) is a transmembrane glycoprotein recently implicated in kidney fibrosis. Previously, we reported that the AREG-targeting Self-Assembled-Micelle inhibitory RNA (SAMiRNA-AREG) alleviated fibrosis by stably silencing the AREG gene, and reduced the side effects of conventional siRNA treatment of pulmonary fibrosis. However, the therapeutic effect of SAMiRNA-AREG in renal fibrosis has not been studied until now. We used two animal models of renal fibrosis generated by a unilateral ureteral obstruction (UUO) and an adenine diet (AD) to investigate whether SAMiRNA-AREG inhibited renal fibrosis. To investigate the delivery of SAMiRNA-AREG to the kidney, Cy5-labeled SAMiRNA-AREG was injected into UUO- and AD-induced renal fibrosis models. In both kidney disease models, SAMiRNA-AREG was delivered primarily to the damaged kidney. We also confirmed the protective effect of SAMiRNA-AREG in renal fibrosis models. SAMiRNA-AREG markedly decreased the UUO- and AD-induced AREG mRNA expression. Furthermore, the mRNA expression of fibrosis markers, including alpha -smooth muscle actin, fibronectin, alpha 1(I) collagen, and alpha 1(III) collagen in the UUO and AD-induced kidneys, was diminished in the SAMiRNA-AREG-treated mice. The transcription of inflammatory markers (tumor necrosis factor-alpha and monocyte chemoattractant protein-1) and adhesion markers (vascular cell adhesion molecule 1 and intercellular adhesion molecule 1) was attenuated. The hematoxylin and eosin, Masson's trichrome, and immunohistochemical staining results showed that SAMiRNA-AREG decreased renal fibrosis, AREG expression, and epidermal growth factor receptor (EGFR) phosphorylation in the UUO- and AD-induced models. Moreover, we studied the effects of SAMiRNA-AREG in response to TGF-beta 1 in mouse and human proximal tubule cells, and mouse fibroblasts. TGF-beta 1-induced extracellular matrix production and myofibroblast differentiation were attenuated by SAMiRNA-AREG. Finally, we confirmed that upregulated AREG in the UUO or AD models was mainly localized in the distal tubules. In conclusion, SAMiRNA-AREG represents a novel siRNA therapeutic for renal fibrosis by suppressing EGFR signals.
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Collections - College of Medicine > Department of Internal Medicine > 1. Journal Articles
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