Kim Jin Won, Nam Sun Ah, Koh Eun-Sil, Kim Hyung Wook, Kim Sua, Woo Jin Ju, Kim Yong Kyun
Department of Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
Antioxidants (Basel). 2024 Jul 23;13(8):886. doi: 10.3390/antiox13080886.
Autophagy is a cellular process that degrades damaged cytoplasmic components and regulates cell death. The homeostasis of endothelial cells (ECs) is crucial for the preservation of glomerular structure and function in aging. Here, we investigated the precise mechanisms of endothelial autophagy in renal aging. The genetic deletion of Atg7 in the ECs of Atg7;Tie2-Cre mice accelerated aging-related glomerulopathy and tubulointerstitial fibrosis. The EC-specific Atg7 deletion in aging mice induced the detachment of EC with the disruption of glomerular basement membrane (GBM) assembly and increased podocyte loss resulting in microalbuminuria. A Transwell co-culture system of ECs and kidney organoids showed that the iron and oxidative stress induce the disruption of the endothelial barrier and increase vascular permeability, which was accelerated by the inhibition of autophagy. This resulted in the leakage of iron through the endothelial barrier into kidney organoids and increased oxidative stress, which led to ferroptotic cell death. The ferritin accumulation was increased in the kidneys of the EC-specific Atg7-deficient aging mice and upregulated the NLRP3 inflammasome signaling pathway. The pharmacologic inhibition of ferroptosis with liproxstatin-1 recovered the disrupted endothelial barrier and reversed the decreased expression of GPX4, as well as NLRP3 and IL-1β, in endothelial autophagy-deficient aged mice, which attenuated aging-related renal injury including the apoptosis of renal cells, abnormal structures of GBM, and tubulointerstitial fibrosis. Our data showed that endothelial autophagy is essential for the maintenance of the endothelial barrier during renal aging and the impairment of endothelial autophagy accelerates renal senescence by ferroptosis and NLRP3 inflammasome signaling pathways. These processes may be attractive therapeutic targets to reduce cellular injury from renal aging.
自噬是一种细胞过程，可降解受损的细胞质成分并调节细胞死亡。内皮细胞（ECs）的稳态对于衰老过程中肾小球结构和功能的维持至关重要。在此，我们研究了肾脏衰老过程中内皮自噬的精确机制。Atg7;Tie2-Cre小鼠内皮细胞中Atg7的基因缺失加速了衰老相关的肾小球病和肾小管间质纤维化。衰老小鼠中内皮细胞特异性Atg7缺失导致内皮细胞脱离，肾小球基底膜（GBM）组装破坏，足细胞丢失增加，导致微量白蛋白尿。内皮细胞与肾脏类器官的Transwell共培养系统表明，铁和氧化应激诱导内皮屏障破坏并增加血管通透性，自噬抑制会加速这种情况。这导致铁通过内皮屏障泄漏到肾脏类器官中并增加氧化应激，从而导致铁死亡细胞死亡。内皮细胞特异性Atg7缺陷衰老小鼠的肾脏中铁蛋白积累增加，并上调了NLRP3炎性小体信号通路。用liproxstatin-1对铁死亡进行药理抑制可恢复内皮屏障破坏，并逆转内皮自噬缺陷老年小鼠中GPX4、NLRP3和IL-1β表达的降低，减轻衰老相关的肾脏损伤，包括肾细胞凋亡、GBM结构异常和肾小管间质纤维化。我们的数据表明，内皮自噬对于肾脏衰老过程中内皮屏障的维持至关重要，内皮自噬受损通过铁死亡和NLRP3炎性小体信号通路加速肾脏衰老。这些过程可能是减少肾脏衰老细胞损伤的有吸引力的治疗靶点。
