Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice
Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice
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DOI：
10.1172/jci39492
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发表时间：
2010-04-01
影响因子：
15.9
通讯作者：
Huber, Tobias B.
中科院分区：
文献类型：
--
作者：
Hartleben, Bjoern;Goedel, Markus;Huber, Tobias B.
足细胞的损伤和丢失是肾小球疾病和肾衰竭的主要因素。有丝分裂后足细胞是毒性、免疫、代谢和氧化应激的主要肾小球靶点，但人们对这种细胞类型如何应对应激知之甚少。近年来，自噬已被确定为将受损的蛋白质和细胞器传递给溶酶体以维持细胞稳态的主要途径。在这里，我们报告足细胞表现出异常高水平的组成性自噬。细胞特异性缺失自噬相关5 （Atg5）导致衰老小鼠肾小球病变，并伴有氧化和泛素化的积累。蛋白质，内质网应激和蛋白尿这些变化最终导致足细胞减少和迟发性肾小球硬化。病理生理条件分析表明，诱导蛋白尿小鼠肾小球和获得性蛋白尿疾病患者肾小球的自噬显著增加。此外，足细胞中缺乏Atg5的小鼠对肾小球疾病模型的易感性明显增加。这些发现强调了诱导自噬作为维持足细胞完整性的关键稳态机制的重要性。我们假设构成性和诱导性自噬是防止足细胞老化和肾小球损伤的主要保护机制，代表了改善人类肾小球疾病和衰老相关肾功能丧失的假设目标。
Injury and loss of podocytes are leading factors of glomerular disease and renal failure. The postmitotic podocyte is the primary glomerular target for toxic, immune, metabolic, and oxidant stress, but little is known about how this cell type copes with stress. Recently, autophagy has been identified as a major pathway that delivers damaged proteins and organelles to lysosomes in order to maintain cellular homeostasis. Here we report that podocytes exhibit an unusually high level of constitutive autophagy. Poclocyte-specific deletion of autophagy-related 5 (Atg5) led to a glomerulopathy in aging mice that was accompanied by an accumulation of oxidized and ubiquitinated. proteins, ER stress, and proteinuria. These changes resulted ultimately in podocyte loss and late-onset glomerulosclerosis. Analysis of pathophysiological conditions indicated that autophagy was substantially increased in glomeruli from mice with induced proteinuria and in glomeruli from patients with acquired proteinuric diseases. Further, mice lacking Atg5 in podocytes exhibited strongly increased susceptibility to models of glomerular disease. These findings highlight the importance of induced autophagy as a key homeostatic mechanism to maintain podocyte integrity. We postulate that constitutive and induced autophagy is a major protective mechanism against podocyte aging and glomerular injury, representing a putative target to ameliorate human glomerular disease and aging-related loss of renal function.