Profibrotic proximal tubules (PT) were identified as a unique phenotype of proximal tubule cells (PTCs) in renal fibrosis by single-cell RNA sequencing (scRNA-seq). Controlling the process of renal fibrosis requires understanding how to manage the S1 subset's branch to the S3 subset rather than to the profibrotic PT subset. Insulin-induced gene 1 (Insig1) is one of the branch-dependent genes involved in controlling this process, although its role in renal fibrosis is unknown. Here, we discovered that tubular Insig1 deficiency, rather than fibroblast Insig1 deficiency, plays a detrimental role in the pathogenesis of renal fibrosis in vivo and in vitro. Overexpression of Insig1 profoundly inhibited renal fibrosis. Mechanistically, Insig1 deletion in PTCs boosted SREBP1 nuclear localization, increasing Aldh1a1 transcriptional activity, causing excessive NAD+ consumption and ER enlargement, as well as accelerating renal fibrosis. We also identified nicardipine as a selective inhibitor of Aldh1a1, which could restore NAD+ and maintain ER homeostasis, as well as improve renal fibrosis. Together, our findings support tubular Insig1 as a new therapeutic target for chronic kidney disease (CKD).

中文翻译：

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肾小管胰岛素诱导的基因 1 缺陷促进 NAD+ 消耗并加剧肾纤维化。


通过单细胞 RNA 测序 （scRNA-seq） 将促纤维化近端小管 （PT） 鉴定为肾纤维化中近端小管细胞 （PTC） 的独特表型。控制肾纤维化的过程需要了解如何管理 S1 亚群到 S3 亚群的分支，而不是到促纤维化 PT 亚群。胰岛素诱导的基因 1 （Insig1） 是参与控制这一过程的分支依赖性基因之一，尽管它在肾纤维化中的作用尚不清楚。在这里，我们发现肾小管 Insig1 缺陷，而不是成纤维细胞 Insig1 缺陷，在体内和体外肾纤维化的发病机制中起着有害作用。Insig1 的过表达严重抑制了肾纤维化。从机制上讲，PTC 中的 Insig1 缺失促进了 SREBP1 核定位，增加了 Aldh1a1 转录活性，导致 NAD+ 过度消耗和 ER 扩大，以及加速肾纤维化。我们还确定尼卡地平是 Aldh1a1 的选择性抑制剂，可以恢复 NAD+ 并维持 ER 稳态，以及改善肾纤维化。总之，我们的研究结果支持肾小管 Insig1 作为慢性肾脏病 （CKD） 的新治疗靶点。