YAP1 preserves tubular mitochondrial quality control to mitigate diabetic kidney disease

作者：Siyang Ye, Meng Zhang, Xunhua Zheng, Suchun Li, Yuting Fan, Yiqin Wang, Huajing Peng, Sixiu Chen, Jiayi Yang, Ying Li, Manhuai Zhang, Peng Xie, Xiaoyan Li, Ning Luo, Zhipeng Wang, Leigang Jin, Xiaoping Wu, Yong Pan, Jinjin Fan, Yi Zhou, Sydney Tang, Бин Ли, Wei Chen · 发表于：Redox Biology · 年份：2024 · DOI：10.1016/j.redox.2024.103435 · 被引用次数：24 · 研究领域：Hippo pathway signaling and YAP/TAZ、Chronic Kidney Disease and Diabetes、Mitochondrial Function and Pathology

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...