MiR-185-5p ameliorates endoplasmic reticulum stress and renal fibrosis by downregulation of ATF6
MiR-185-5p ameliorates endoplasmic reticulum stress and renal fibrosis by downregulation of ATF6
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DOI：
10.1038/s41374-020-0447-y
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发表时间：
2020-06
影响因子：
5
通讯作者：
Q. Yuan;Tianhua Xu;Y. Chen;Wei Qu;Dan Sun;Xiaodan Liu;Li Sun
中科院分区：
文献类型：
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作者：
Q. Yuan;Tianhua Xu;Y. Chen;Wei Qu;Dan Sun;Xiaodan Liu;Li Sun
内质网（ER）应激被认为是纤维化形成的重要因素。因此，调节ER应激可能代表肾纤维化的有希望的治疗策略。miR-185- 5 p已被确定参与TGF-β1诱导的肾纤维化;然而，miR-185- 5 p是否以及如何调节肾纤维化中的ER应激在很大程度上是未知的。在本研究中，我们证明了miR-185- 5 p直接与ER应激相关蛋白ATF 6结合，并下调其表达。我们随后使用TGF-β1处理的HK 2细胞构建了肾纤维化的体外模型，发现miR-185- 5 p通过抑制ATF 6减弱了ER应激和肾小管上皮细胞的去分化。此外，我们还建立了单侧尿道梗阻（UUO）的体内小鼠模型。我们的体内研究结果表明，miR-185- 5 p通过下调ATF 6降低ER应激相关蛋白的表达并抑制上皮去分化，从而改善UUO诱导的肾纤维化。总体而言，我们的研究结果表明，miR-185- 5 p在肾纤维化中发挥有益作用。因此，miR-185- 5 p/ATF 6调控通路可能是肾纤维化治疗干预的潜在靶点。
Endoplasmic reticulum (ER) stress is considered an important factor in the formation of fibrosis. Therefore, modulation of ER stress may represent a promising therapeutic strategy in renal fibrosis. MiR-185-5p has been identified to be implicated in TGF-β1-induced renal fibrosis; however, it is largely unknown whether and how miR-185-5p regulates ER stress in renal fibrosis. In this study, we demonstrated that miR-185-5p directly bound to ATF6, an ER stress-related protein, and downregulated the expression thereof. We subsequently constructed an in vitro model of renal fibrosis using HK2 cells treated with TGF-β1, and found that miR-185-5p attenuated ER stress and dedifferentiation of tubular epithelia by suppression of ATF6. In addition, we constructed an in vivo mouse model using unilateral urethral obstruction (UUO). Our in vivo findings showed that miR-185-5p reduced the expression of ER stress-related proteins and inhibited epithelial dedifferentiation via downregulation of ATF6, thereby improving UUO-induced renal fibrosis. Overall, our findings revealed that miR-185-5p exerts beneficial effects in renal fibrosis. Thus, the miR-185-5p/ATF6 regulatory pathway may be a potential target for therapeutic intervention in renal fibrosis.