Angiotensin-Converting Enzyme-Dependent Intrarenal Angiotensin II Contributes to CTP: Phosphoethanolamine Cytidylyltransferase Downregulation, Mitochondrial Membranous Disruption, and Reactive Oxygen Species Overgeneration in Diabetic Tubulopathy

作者：Xia-Qing Li, Xia-Qing Li, Zhang-Zhang Xiao, Zhang-Zhang Xiao, Ke Ma, X.-L. Liu, Huan‐Huan Liu, Bo Hu, Qian Zhao, Hong-Yue Li, Ruichang Chen, Ruichang Chen, Yu Meng, Liang-Hong Yin, Lianghong Yin · 发表于：Antioxidants and Redox Signaling · 年份：2024 · DOI：10.1089/ars.2024.0637 · 被引用次数：4 · 研究领域：Alcohol Consumption and Health Effects、Neurological and metabolic disorders、Metabolism and Genetic Disorders

Aims:The limited therapeutic options for diabetic tubulopathy (DT) in early diabetic kidney disease (DKD) reflect the difficulty of targeting renal tubular compartment. While renin–angiotensin–aldosterone system (RAS) inhibitors are commonly utilized in the management of DKD, how intrarenal RAS contributes to diabetic tubular injury is not fully understood. Mitochondrial disruption and reactive oxygen species (ROS) overgeneration have been involved in diabetic tubular injury. Herein, we aim to test the hypothesis that angiotensin-converting enzyme (ACE)-dependent intrarenal angiotensin II (AngII) disrupts tubular mitochondrial membranous homeostasis and causes excessive ROS generation in DT. Results:Mice suffered from renal tubular mitochondrial disruption and ROS overgeneration following high-fat diet/streptozocin-type 2 diabetic induction. Intrarenal AngII generation is ACE-dependent in DT. Local AngII accumulation in renal tissues was achieved by intrarenal artery injection. ACE-dependent intrarenal AngII-treated mice exhibit markedly elevated levels of makers of tubular injury. CTP: Phosphoethanolamine cytidylyltransferase (PCYT2), the primary regulatory enzyme for the biosynthesis of phosphatidylethanolamine, was enriched in renal tubules according to single-cell RNA sequencing. ACE-dependent intrarenal AngII-induced tubular membranous disruption, ROS overgeneration, and PCYT2 downregulation. The diabetic ambiance deteriorated the detrimental effect of ACE-dependent intr...