Li Xia-Qing, Xiao Zhang-Zhang, Ma Ke, Liu Xia-Yun, Liu Huan-Huan, Hu Bo, Zhao Qian, Li Hong-Yue, Chen Rui-Chang, Meng Yu, Yin Liang-Hong
Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China.
Nephrology Department, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, China.
Antioxid Redox Signal. 2025 May;42(13-15):767-786. doi: 10.1089/ars.2024.0637. Epub 2024 Nov 4.
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. 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 intrarenal AngII on renal tubules. Captopril, the ACE inhibitor (ACEI), showed efficiency in partially ameliorating ACE-dependent intrarenal AngII-induced tubular deterioration pre- and post-diabetic induction. This study uncovers a critical role of ACE-dependent intrarenal AngII in mitochondrial membranous disruption, ROS overgeneration, and PCYT2 deficiency in diabetic renal tubules, providing novel insight into DT pathogenesis and ACEI-combined therapeutic targets. 42, 767-786.
早期糖尿病肾病（DKD）中糖尿病肾小管病变（DT）的治疗选择有限，这反映了针对肾小管区域进行治疗的困难。虽然肾素-血管紧张素-醛固酮系统（RAS）抑制剂常用于DKD的管理，但肾内RAS如何导致糖尿病肾小管损伤尚未完全明确。线粒体破坏和活性氧（ROS）过度生成与糖尿病肾小管损伤有关。在此，我们旨在验证以下假设：血管紧张素转换酶（ACE）依赖性肾内血管紧张素II（AngII）破坏肾小管线粒体膜稳态并导致DT中ROS过度生成。高脂饮食/链脲佐菌素诱导的2型糖尿病小鼠出现肾小管线粒体破坏和ROS过度生成。DT中肾内AngII的生成依赖于ACE。通过肾动脉注射实现肾组织中局部AngII的蓄积。ACE依赖性肾内AngII处理的小鼠肾小管损伤标志物水平显著升高。根据单细胞RNA测序，CTP：磷酸乙醇胺胞苷转移酶（PCYT2）是磷脂酰乙醇胺生物合成的主要调节酶，在肾小管中富集。ACE依赖性肾内AngII诱导肾小管膜破坏、ROS过度生成和PCYT2下调。糖尿病环境加剧了ACE依赖性肾内AngII对肾小管的有害影响。ACE抑制剂（ACEI）卡托普利在糖尿病诱导前后均能部分改善ACE依赖性肾内AngII诱导的肾小管恶化。本研究揭示了ACE依赖性肾内AngII在糖尿病肾小管线粒体膜破坏、ROS过度生成和PCYT2缺乏中的关键作用，为DT发病机制和ACEI联合治疗靶点提供了新的见解。42, 767 - 786。
