YAP1 preserves tubular mitochondrial quality control to mitigate diabetic kidney disease

• Published in: Redox biology Vol. 78; p. 103435
• Main Authors: Ye, Siyang, Zhang, Meng, Zheng, Xunhua, Li, Suchun, Fan, Yuting, Wang, Yiqin, Peng, Huajing, Chen, Sixiu, Yang, Jiayi, Tan, Li, Zhang, Manhuai, Xie, Peichen, Li, Xiaoyan, Luo, Ning, Wang, Zhipeng, Jin, Leigang, Wu, Xiaoping, Pan, Yong, Fan, Jinjin, Zhou, Yi, Tang, Sydney C.W., Li, Bin, Chen, Wei
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2024; Elsevier
• Subjects: Animals; Chemokine; Diabetic kidney disease; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Hippo signaling pathway; Humans; Kidney Tubules - metabolism; Kidney Tubules - pathology; Macrophage; Male; Mice; Mitochondria; Mitochondria - metabolism; Mitophagy; Research Paper; YAP-Signaling Proteins - metabolism; Yes-associated protein 1; Chemokine; Mitochondria; Hippo signaling pathway; Yes-associated protein 1; Diabetic kidney disease; Macrophage
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2024.103435

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. [Display omitted] •A robust diagnostic model incorporating YAP1 and mitochondrial quality control (MQC)-related genes demonstrates high accuracy in detecting DKD.•In DKD, YAP1 inactivation correlates with impaired MQC in renal tubule cells.•Deletion of Yap1 in tubule cells disrupts MQC, leading to increased secretion of CXCL1 and ultimately enhanced macrophage infiltration.•YAP1 activation preserves MQC homeostasis, subsequently reducing renal injury and M1 macrophage infiltration.•Targeting the Hippo signaling pathway shows promise in DKD prevention and treatment by addressing YAP1 inactivation-mediated MQC dysfunction in renal tubule cells.