Impaired Lysosomal Function Underlies Monoclonal Light Chain-Associated Renal Fanconi Syndrome
Impaired Lysosomal Function Underlies Monoclonal Light Chain-Associated Renal Fanconi Syndrome
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DOI：
10.1681/asn.2015050581
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发表时间：
2016-07-01
影响因子：
13.6
通讯作者：
Devuyst, Olivier
中科院分区：
文献类型：
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作者：
Luciani, Alessandro;Sirac, Christophe;Devuyst, Olivier
单克隆丙种球蛋白病经常并发肾脏病变，从而增加疾病的发病率和死亡率。特别是，异常的 Ig 游离轻链 (LC) 可能在上皮细胞内积聚，导致近端小管 (PT) 功能障碍和肾范可尼综合征 (RFS)。为了研究 LC 积累和 PT 功能障碍之间的联系机制，我们使用了过度表达人类对照或 RFS 相关 kappa LC (RFS-kappa LC) 的转基因小鼠以及暴露于低剂量相应人 kappa LC (25 μg/ml) 的小鼠 PT 细胞的原代培养物。在肾衰竭发生之前，过度表达 RFS-kappa LC 的小鼠表现出与顶端转运蛋白和受体丧失相关的 PT 功能障碍，以及与 kappa LC 溶酶体积累相关的 PT 细胞增殖率增加。 PT 细胞暴露于 RFS-kappa LC 会导致 kappa LC 在扩大和功能失调的溶酶体中积累、细胞动力学改变、蛋白水解和水解酶成熟缺陷以及溶酶体酸化受损。这些变化是 RFS-kappa LC 可变 (V) 序列特有的，因为对照 LC 或在 V 结构域中携带单一取代（Ala30 -> Ser）的相同 RFS-kappa LC 不会发生这些变化。 RFS-kappa LC 诱导的溶酶体改变反映在细胞增殖增加、内吞受体顶端表达减少和内吞作用缺陷。这些结果表明，特定的 kappa LC 在溶酶体内积累，通过有缺陷的酸化改变溶酶体动力学和蛋白水解功能，从而导致 PT 细胞去分化和重吸收能力丧失。这些早期事件的特征与先天性溶酶体疾病中遇到的相似，为报道的差异性 LC 毒性和 LC 诱导的 RFS 的新观点提供了基础。
Monoclonal gammopathies are frequently complicated by kidney lesions that increase the disease morbidity and mortality. In particular, abnormal Ig free light chains (LCs) may accumulate within epithelial cells, causing proximal tubule (PT) dysfunction and renal Fanconi syndrome (RFS). To investigate the mechanisms linking LC accumulation and PT dysfunction, we used transgenic mice overexpressing human control or RFS-associated kappa LCs (RFS-kappa LCs) and primary cultures of mouse PT cells exposed to low doses of corresponding human kappa LCs (25 mu g/ml). Before the onset of renal failure, mice overexpressing RFS-kappa LCs showed PT dysfunction related to loss of apical transporters and receptors and increased PT cell proliferation rates associated with lysosomal accumulation of kappa LCs. Exposure of PT cells to RFS-kappa LCs resulted in kappa LC accumulation within enlarged and dysfunctional lysosomes, alteration of cellular dynamics, defective proteolysis and hydrolase maturation, and impaired lysosomal acidification. These changes were specific to the RFS-kappa LC variable (V) sequence, because they did not occur with control LCs or the same RFS-kappa LC carrying a single substitution (Ala30 -> Ser) in the V domain. The lysosomal alterations induced by RFS-kappa LCs were reflected in increased cell proliferation, decreased apical expression of endocytic receptors, and defective endocytosis. These results reveal that specific kappa LCs accumulate within lysosomes, altering lysosome dynamics and proteolytic function through defective acidification, thereby causing dedifferentiation and loss of reabsorptive capacity of PT cells. The characterization of these early events, which are similar to those encountered in congenital lysosomal disorders, provides a basis for the reported differential LC toxicity and new perspectives on LC-induced RFS.