Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis.
Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis.
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Brahma相关基因1通过Wnt/β-catenin/自噬轴促进肾小管衰老和肾纤维化
DOI：
10.1042/cs20210447
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发表时间：
2021-08-13
期刊：
影响因子：
--
通讯作者：
Long H
中科院分区：
文献类型：
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作者：
Gong W;Luo C;Peng F;Xiao J;Zeng Y;Yin B;Chen X;Li S;He X;Liu Y;Cao H;Xu J;Long H
尽管细胞加速衰老与慢性肾脏病（CKD）和肾纤维化的进展密切相关，但其潜在机制仍不清楚。在这里，我们报告了肾小管Brahma相关基因1（BRG 1）的异常表达，SWITCH/蔗糖非发酵复合物的酶亚基，是至关重要的参与肾小管衰老和肾纤维化。BRG 1在CKD患者和单侧输尿管梗阻（UUO）小鼠的肾脏中显著上调，主要在肾小管上皮细胞中。在体内，shRNA介导的BRG 1敲低显著改善肾纤维化，改善肾小管衰老，并抑制UUO诱导的Wnt/β-catenin通路活化。在小鼠肾小管上皮细胞（mTEC）和原代肾小管细胞中，抑制BRG 1可减少转化生长因子-β1（TGF-β1）诱导的细胞衰老和纤维化反应。相应地，在mTECs或正常肾脏中BRG 1的异位表达增加了p16 INK 4a、p19 ARF和p21的表达以及衰老相关的β-半乳糖苷酶（SA-β-gal）活性，表明加速了肾小管衰老。此外，BRG 1介导的促纤维化反应在很大程度上被体外小干扰RNA（siRNA）介导的p16 INK 4a沉默或体内ABT-263连续衰老清除治疗所消除。此外，BRG 1激活Wnt/β-catenin通路，这进一步抑制自噬。药理学抑制Wnt/β-catenin途径（ICG-001）或雷帕霉素（RAPA）介导的自噬激活可有效阻断BRG 1诱导的肾小管衰老和纤维化反应，而巴弗洛霉素A1（Baf A1）介导的自噬抑制可消除ICG-001的作用。此外，BRG 1改变了衰老肾小管细胞的分泌组，这促进了成纤维细胞的增殖和活化。综上所述，我们的结果表明，BRG 1通过Wnt/β-catenin途径抑制自噬诱导肾小管衰老，最终导致肾纤维化的发展。
Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWItch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly up-regulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/β-catenin pathway. In mouse renal tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished transforming growth factor-β1 (TGF-β1)-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs or normal kidneys increased p16INK4a, p19ARF, and p21 expression and senescence-associated β-galactosidase (SA-β-gal) activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by small interfering RNA (siRNA)-mediated p16INK4a silencing in vitro or continuous senolytic treatment with ABT-263 in vivo. Moreover, BRG1 activated the Wnt/β-catenin pathway, which further inhibited autophagy. Pharmacologic inhibition of the Wnt/β-catenin pathway (ICG-001) or rapamycin (RAPA)-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1 (Baf A1)-mediated inhibition of autophagy abolished the effects of ICG-001. Further, BRG1 altered the secretome of senescent tubular cells, which promoted proliferation and activation of fibroblasts. Taken together, our results indicate that BRG1 induces tubular senescence by inhibiting autophagy via the Wnt/β-catenin pathway, which ultimately contributes to the development of renal fibrosis.