Imai Kentaro, Ishimoto Takuji, Doke Tomohito, Tsuboi Toshiki, Watanabe Yu, Katsushima Keisuke, Suzuki Miho, Oishi Hideto, Furuhashi Kazuhiro, Ito Yasuhiko, Kondo Yutaka, Maruyama Shoichi
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Aichi, 480-1195, Japan.
Mol Ther Nucleic Acids. 2022 Dec 23;31:139-150. doi: 10.1016/j.omtn.2022.12.011. eCollection 2023 Mar 14.
Renal interstitial fibrosis (RIF) is a common pathological manifestation of chronic kidney diseases. Epithelial-mesenchymal transition (EMT) of tubular epithelial cells is considered a major cause of RIF. Although long non-coding RNAs (lncRNAs) are reportedly involved in various pathophysiological processes, the roles and underlying molecular mechanisms of lncRNAs in the progression of RIF are poorly understood. In this study, we investigated the function of lncRNAs in RIF. Microarray assays showed that expression of the lncRNA lnc-CHAF1B-3 (also called claudin 14 antisense RNA 1) was significantly upregulated in human renal proximal tubular cells by both transforming growth factor-β1 (TGF-β1) and hypoxic stimulation, accompanied with increased expression of EMT-related genes. Knockdown of lnc-CHAF1B-3 significantly suppressed TGF-β1-induced upregulated expression of collagen type I alpha 1, cadherin-2, plasminogen activator inhibitor-1, snail family transcriptional repressor I (SNAI1) and SNAI2. Quantitative reverse transcriptase PCR analyses of paraffin-embedded kidney biopsy samples from IgA nephropathy patients revealed lnc-CHAF1B-3 expression was correlated positively with urinary protein levels and correlated negatively with estimated glomerular filtration rate. hybridization demonstrated that lnc-CHAF1B-3 is expressed only in proximal tubules. These findings suggest lnc-CHAF1B-3 affects the progression of RIF by regulating EMT-related signaling. Thus, lnc-CHAF1B-3 is a potential target in the treatment of RIF.
肾间质纤维化（RIF）是慢性肾脏病常见的病理表现。肾小管上皮细胞的上皮-间质转化（EMT）被认为是RIF的主要原因。尽管据报道长链非编码RNA（lncRNAs）参与各种病理生理过程，但lncRNAs在RIF进展中的作用及潜在分子机制仍知之甚少。在本研究中，我们调查了lncRNAs在RIF中的功能。微阵列分析显示，lncRNA lnc-CHAF1B-3（也称为claudin 14反义RNA 1）在人肾近端小管细胞中经转化生长因子-β1（TGF-β1）和缺氧刺激后表达显著上调，同时EMT相关基因的表达增加。敲低lnc-CHAF1B-3可显著抑制TGF-β1诱导的I型胶原α1、钙黏蛋白-2、纤溶酶原激活物抑制剂-1、蜗牛家族转录抑制因子I（SNAI1）和SNAI2的表达上调。对IgA肾病患者石蜡包埋肾活检样本进行的定量逆转录PCR分析显示，lnc-CHAF1B-3表达与尿蛋白水平呈正相关，与估计肾小球滤过率呈负相关。原位杂交表明lnc-CHAF1B-3仅在近端小管中表达。这些发现提示lnc-CHAF1B-3通过调节EMT相关信号通路影响RIF的进展。因此，lnc-CHAF1B-3是RIF治疗的潜在靶点。
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