Autophagy Inhibits the Accumulation of Advanced Glycation End Products by Promoting Lysosomal Biogenesis and Function in the Kidney Proximal Tubules
Autophagy Inhibits the Accumulation of Advanced Glycation End Products by Promoting Lysosomal Biogenesis and Function in the Kidney Proximal Tubules
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DOI：
10.2337/db16-0397
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发表时间：
2017-05-01
期刊：
影响因子：
7.7
通讯作者：
Isaka, Yoshitaka
中科院分区：
文献类型：
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作者：
Takahashi, Atsushi;Takabatake, Yoshitsugu;Isaka, Yoshitaka
晚期糖基化终产物（AGEs）参与糖尿病肾病的进展。AGEs经肾小球过滤或从循环中释放后，在近端肾小管上皮细胞（PTECs）的溶酶体中被内吞和降解。自噬是一种高度保守的降解系统，通过吞噬细胞质成分来调节细胞内稳态。我们最近证明，在某些情况下，受损溶酶体的自噬降解对于细胞内稳态是不可或缺的。在这项研究中，我们测试的假设，自噬可以通过调节溶酶体的生物合成在糖尿病肾脏AGEs的降解。高糖和外源性AGE超负荷逐渐减弱培养的PTECs中的自噬通量。AGE超负荷上调体外溶酶体的生物合成和功能，这在自噬缺陷的PTECs中由于转录因子EB的核转位受损而被抑制。一致的是，链脲佐菌素处理的，PTEC特异性，自噬缺陷小鼠未能上调溶酶体生物合成，并表现出在肾小球和肾血管系统以及PTEC中的AGEs积累，沿着恶化的炎症和纤维化。这些结果表明，自噬有助于通过上调溶酶体的生物合成和功能在糖尿病肾病中的AGEs的降解。旨在促进溶酶体功能的策略有望治疗糖尿病肾病。
Advanced glycation end products (AGEs) are involved in the progression of diabetic nephropathy. AGEs filtered by glomeruli or delivered from the circulation are endocytosed and degraded in the lysosomes of kidney proximal tubular epithelial cells (PTECs). Autophagy is a highly conserved degradation system that regulates intracellular homeostasis by engulfing cytoplasmic components. We have recently demonstrated that autophagic degradation of damaged lysosomes is indispensable for cellular homeostasis in some settings. In this study, we tested the hypothesis that autophagy could contribute to the degradation of AGEs in the diabetic kidney by modulating lysosomal biogenesis. Both a high-glucose and exogenous AGE overload gradually blunted autophagic flux in the cultured PTECs. AGE overload upregulated lysosomal biogenesis and function in vitro, which was inhibited in autophagy-deficient PTECs because of the impaired nuclear translocation of transcription factor EB. Consistently, streptozotocin-treated, PTEC-specific, autophagy-deficient mice failed to upregulate lysosomal biogenesis and exhibited the accumulation of AGEs in the glomeruli and renal vasculature as well as in the PTECs, along with worsened inflammation and fibrosis. These results indicate that autophagy contributes to the degradation of AGEs by the upregulation of lysosomal biogenesis and function in diabetic nephropathy. Strategies aimed at promoting lysosomal function hold promise for treating diabetic nephropathy.