Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
Division of Medical Research Planning and Development, Nihon University School of Medicine, Tokyo, Japan.
Am J Physiol Renal Physiol. 2024 Nov 1;327(5):F739-F757. doi: 10.1152/ajprenal.00026.2024. Epub 2024 Sep 19.
Oxidative stress mediated by reactive oxygen species (ROS) contributes to apoptosis of tubular epithelial cells (TECs) and renal inflammation during acute kidney injury (AKI). Copper metabolism MURR1 domain-containing 5 [COMMD5/hypertension-related, calcium-regulated gene (HCaRG)] shows strong cytoprotective properties. COMMD5 is highly expressed in proximal tubules (PTs), where it controls cell differentiation. We assessed its role in cisplatin-induced AKI using transgenic mice in which COMMD5 is overexpressed in the PTs. Cisplatin caused the accumulation of damaged mitochondria and cellular waste in PTs, thus increasing the apoptosis of TECs. COMMD5 overexpression effectively protected TECs from cisplatin nephrotoxicity by decreasing intracellular ROS levels, mitochondrial dysfunction, and apoptosis through the preservation of tubular epithelial integrity, thus alleviating morphological and functional kidney damage. Excessive ROS production by hydrogen peroxide led to long-term autophagy activation through an increased burden on the autophagy/lysosome degradation system in TECs, and autophagic elimination of damaged mitochondria and cellular waste was compromised. COMMD5 attenuated oxidative injury by increasing autophagy flux, possibly due to a reduction of intracellular ROS levels through maintained tubular epithelial integrity, which decreased JNK/caspase-3-dependent apoptosis. Meanwhile, COMMD5 inhibition by siRNA reduced the resistance of TECs to cisplatin cytotoxicity, as shown by disrupted tubular epithelial integrity and cell viability. These data indicated that COMMD5 protects TECs from drug-induced oxidative stress and toxicity by maintaining tubular epithelial integrity and autophagy flux and ultimately decreases mitochondrial dysfunction and apoptosis. Increasing COMMD5 content in PTs is proposed as a new protective and therapeutic strategy against AKI. Oxidative stress overload by drug treatment causes the accumulation of damaged mitochondria that could contribute to tubulopathy. However, effective preventive treatment for drug-induced acute kidney injury remains incompletely understood. Our study showed that copper metabolism MURR1 domain-containing 5 (COMMD5) reduced mitochondrial dysfunction and increased autophagy flux by alleviating reactive oxygen species production through maintaining tubular epithelial integrity when tubular epithelial cells were under oxidative stress, thus ameliorating renal function in cisplatin-treated mice. These results uncover a novel renoprotective mechanism underlying tubular epithelial integrity and autophagy flux.
活性氧（ROS）介导的氧化应激导致急性肾损伤（AKI）期间肾小管上皮细胞（TEC）凋亡和肾脏炎症。铜代谢 MURR1 结构域包含 5 [COMMD5/高血压相关、钙调节基因（HCaRG）] 表现出强烈的细胞保护特性。COMMD5 在近端肾小管（PT）中高度表达，控制细胞分化。我们使用 COMMD5 在 PT 中过表达的转基因小鼠评估了其在顺铂诱导的 AKI 中的作用。顺铂导致 PT 中受损线粒体和细胞废物的积累，从而增加 TEC 的凋亡。COMMD5 过表达通过保持管状上皮完整性有效保护 TEC 免受顺铂肾毒性，从而降低细胞内 ROS 水平、线粒体功能障碍和凋亡，从而减轻形态和功能肾损伤。TEC 中自噬/溶酶体降解系统负担增加导致过氧化氢产生的过多 ROS 导致长期自噬激活，并且受损线粒体和细胞废物的自噬消除受损。COMMD5 通过增加自噬通量减轻氧化损伤，可能是由于通过保持管状上皮完整性降低细胞内 ROS 水平，从而减少 JNK/caspase-3 依赖性凋亡。同时，siRNA 抑制 COMMD5 降低了 TEC 对顺铂细胞毒性的抵抗力，表现为管状上皮完整性破坏和细胞活力降低。这些数据表明，COMMD5 通过维持管状上皮完整性和自噬通量来保护 TEC 免受药物引起的氧化应激和毒性，最终减少线粒体功能障碍和凋亡。增加 PT 中的 COMMD5 含量被提议作为一种新的针对 AKI 的保护和治疗策略。药物治疗引起的氧化应激过载导致受损线粒体的积累，这可能导致肾小管病变。然而，药物引起的急性肾损伤的有效预防治疗仍不完全了解。我们的研究表明，铜代谢 MURR1 结构域包含 5（COMMD5）通过维持管状上皮完整性减轻活性氧产生来减轻线粒体功能障碍并增加自噬通量，从而改善顺铂处理的小鼠的肾功能。这些结果揭示了管状上皮完整性和自噬通量的新的肾脏保护机制。
