Renal tubule cells act as a primary site of injury in diabetic kidney disease (DKD), with dysfunctional mitochondrial quality control (MQC) closely associated with progressive kidney dysfunction in this context. Our investigation delves into the observed inactivation of yes-associated protein 1 (YAP1) and consequential dysregulation of MQC within renal tubule cells among DKD subjects through bioinformatic analysis of transcriptomics data from the Gene Expression Omnibus (GEO) dataset. Receiver operating characteristic curve analysis unequivocally underscores the robust diagnostic accuracy of YAP1 and MQC-related genes for DKD. Furthermore, we observed YAP1 inactivation, accompanied by perturbed MQC, within cultured tubule cells exposed to high glucose (HG) and palmitic acid (PA). This pattern was also evident in the tubulointerstitial compartment of kidney sections from biopsy-approved DKD patients. Additionally, renal tubule cell-specific Yap1 deletion exacerbated kidney injury in diabetic mice. Mechanistically, Yap1 deletion disrupted MQC, leading to mitochondrial aberrations in mitobiogenesis and mitophagy within tubule cells, ultimately culminating in histologic tubular injury. Notably, Yap1 deletion-induced renal tubule injury promoted the secretion of C-X-C motif chemokine ligand 1 (CXCL1), potentially augmenting M1 macrophage infiltration within the renal microenvironment. These multifaceted events were significantly ameliorated by administrating the YAP1 activator XMU-MP-1 in DKD mice. Consistently, bioinformatic analysis of transcriptomics data from the GEO dataset revealed a noteworthy upregulation of tubule cells-derived chemokine CXCL1 associated with macrophage infiltration among DKD patients. Crucially, overexpression of YAP1 via adenovirus transfection sustained mitochondrial membrane potential, mtDNA copy number, oxygen consumption rate, and activity of mitochondrial respiratory chain complex, but attenuated mitochondrial ROS production, thereby maintaining MQC and subsequently suppressing CXCL1 generation within cultured tubule cells exposed to HG and PA. Collectively, our study establishes a pivotal role of tubule YAP1 inactivation-mediated MQC dysfunction in driving DKD progression, at least in part, facilitated by promoting M1 macrophage polarization through a paracrine-dependent mechanism.

中文翻译：

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YAP1 保留肾小管线粒体质量控制以减轻糖尿病肾病


肾小管细胞是糖尿病肾病 （DKD） 损伤的主要部位，在这种情况下，功能失调的线粒体质量控制 （MQC） 与进行性肾功能不全密切相关。我们的研究通过对来自基因表达综合 （GEO） 数据集的转录组学数据的生物信息学分析，深入研究了 DKD 受试者观察到的 yes 相关蛋白 1 （YAP1） 失活和随之而来的肾小管细胞内 MQC 失调。受试者工作特征曲线分析明确强调了 YAP1 和 MQC 相关基因对 DKD 的稳健诊断准确性。此外，我们在暴露于高葡萄糖 （HG） 和棕榈酸 （PA） 的培养小管细胞中观察到 YAP1 失活，并伴有 MQC 扰动。这种模式在活检批准的 DKD 患者肾切片的肾小管间质隔室中也很明显。此外，肾小管细胞特异性 Yap1 缺失加剧了糖尿病小鼠的肾损伤。从机制上讲，Yap1 缺失破坏了 MQC，导致肾小管细胞内有丝分裂发生和线粒体自噬的线粒体畸变，最终导致组织学肾小管损伤。值得注意的是，Yap1 缺失诱导的肾小管损伤促进了 C-X-C 基序趋化因子配体 1 （CXCL1） 的分泌，可能增加了肾脏微环境中 M1 巨噬细胞的浸润。通过在 DKD 小鼠中施用 YAP1 激活剂 XMU-MP-1 ，这些多方面事件得到了显著改善。一致地，对来自 GEO 数据集的转录组学数据的生物信息学分析揭示了 DKD 患者与巨噬细胞浸润相关的小管细胞衍生趋化因子 CXCL1 的显着上调。 至关重要的是，通过腺病毒转染过表达 YAP1 维持了线粒体膜电位、mtDNA 拷贝数、耗氧率和线粒体呼吸链复合物的活性，但减弱了线粒体 ROS 的产生，从而维持了 MQC 并随后抑制了暴露于 HG 和 PA 的培养小管细胞内 CXCL1 的产生。总的来说，我们的研究确定了小管 YAP1 失活介导的 MQC 功能障碍在驱动 DKD 进展中的关键作用，至少部分地是通过旁分泌依赖性机制促进 M1 巨噬细胞极化来促进的。