Renal Research Institution of Beijing University of Chinese Medicine, Beijing, China.
Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China.
J Cell Mol Med. 2020 Aug;24(15):8276-8290. doi: 10.1111/jcmm.15301. Epub 2020 Jun 25.
The catabolic process that delivers cytoplasmic constituents to the lysosome for degradation, known as autophagy, is thought to act as a cytoprotective mechanism in response to stress or as a pathogenic process contributing towards cell death. Animal and human studies have shown that autophagy is substantially dysregulated in renal cells in diabetes, suggesting that activating autophagy could be a therapeutic intervention. However, under prolonged hyperglycaemia with impaired lysosome function, increased autophagy induction that exceeds the degradative capacity in cells could contribute toward autophagic stress or even the stagnation of autophagy, leading to renal cytotoxicity. Since lysosomal function is likely key to linking the dual cytoprotective and cytotoxic actions of autophagy, it is important to develop novel pharmacological agents that improve lysosomal function and restore autophagic flux. In this review, we first provide an overview of the autophagic-lysosomal pathway, particularly focusing on stages of lysosomal degradation during autophagy. Then, we discuss the role of adaptive autophagy and autophagic stress based on lysosomal function. More importantly, we focus on the role of autophagic stress induced by lysosomal dysfunction according to the pathogenic factors (including high glucose, advanced glycation end products (AGEs), urinary protein, excessive reactive oxygen species (ROS) and lipid overload) in diabetic kidney disease (DKD), respectively. Finally, therapeutic possibilities aimed at lysosomal restoration in DKD are introduced.
细胞质成分被输送到溶酶体进行降解的分解代谢过程，称为自噬，被认为是一种应激反应的细胞保护机制，或者是导致细胞死亡的致病过程。动物和人类研究表明，糖尿病患者的肾脏细胞中自噬明显失调，这表明激活自噬可能是一种治疗干预措施。然而，在高血糖伴溶酶体功能受损的情况下，过度的自噬诱导超过细胞的降解能力，可能导致自噬应激，甚至自噬停滞，导致肾细胞毒性。由于溶酶体功能可能是连接自噬的双重细胞保护和细胞毒性作用的关键，因此开发能够改善溶酶体功能并恢复自噬流的新型药理学制剂非常重要。在这篇综述中，我们首先概述了自噬溶酶体途径，特别是聚焦于自噬过程中溶酶体降解的阶段。然后，我们根据溶酶体功能讨论了适应性自噬和自噬应激的作用。更重要的是，我们根据糖尿病肾病（DKD）中的致病因素（包括高血糖、晚期糖基化终产物（AGEs）、尿蛋白、过量的活性氧（ROS）和脂质过载），分别关注溶酶体功能障碍诱导的自噬应激的作用。最后，介绍了针对 DKD 中溶酶体恢复的治疗可能性。
