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锂通过激活 mTORC2/蛋白激酶 B 通路改善小管间质损伤。

Lithium ameliorates tubule-interstitial injury through activation of the mTORC2/protein kinase B pathway.

机构信息

Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.

Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brazil.

出版信息

PLoS One. 2019 Apr 19;14(4):e0215871. doi: 10.1371/journal.pone.0215871. eCollection 2019.

DOI:10.1371/journal.pone.0215871
PMID:31002704
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6474631/
Abstract

Tubule-interstitial injury (TII) is a critical step in the progression of renal disease. It has been proposed that changes in proximal tubule (PT) albumin endocytosis plays an important role in the development of TII. Some reports have shown protective effects of lithium on kidney injury animal models that was correlated to proteinuria. We tested the hypothesis that lithium treatment ameliorates the development of TII due to changes in albumin endocytosis. Two experimental models were used: (1) TII induced by albumin overload in an animal model; (2) LLC-PK1 cells, a PT cell line. Lithium treatment ameliorates TII induced by albumin overload measured by (1) proteinuria; (2) collagen deposition; (3) area of tubule-interstitial space, and (4) macrophage infiltration. Lithium treatment increased mTORC2 activity leading to the phosphorylation of protein kinase B (PKB) at Ser473 and its activation. This mechanism enhanced albumin endocytosis in PT cells, which decreased the proteinuria observed in TII induced by albumin overload. This effect did not involve changes in the expression of megalin, a PT albumin receptor. In addition, activation of this pathway decreased apoptosis in LLC-PK1 cells, a PT cell line, induced by higher albumin concentration, similar to that found in pathophysiologic conditions. Our results indicate that the protective role of lithium treatment on TII induced by albumin overload involves an increase in PT albumin endocytosis due to activation of the mTORC2/PKB pathway. These results open new possibilities in understanding the effects of lithium on the progression of renal disease.

摘要

肾小管间质损伤（Tubule-interstitial injury，TII）是肾脏疾病进展的关键步骤。有人提出，近端肾小管（PT）白蛋白内吞作用的变化在 TII 的发展中起着重要作用。一些报告显示，锂对肾病动物模型具有保护作用，这种作用与蛋白尿有关。我们检验了这样一个假设，即锂治疗通过改变白蛋白内吞作用来改善 TII 的发展。我们使用了两种实验模型：（1）白蛋白过载诱导的动物模型中的 TII；（2）LLC-PK1 细胞，一种 PT 细胞系。锂治疗改善了白蛋白过载诱导的 TII，表现在：（1）蛋白尿；（2）胶原沉积；（3）肾小管间质空间面积；（4）巨噬细胞浸润。锂治疗增加了 mTORC2 活性，导致蛋白激酶 B（protein kinase B，PKB）在丝氨酸 473 位磷酸化并激活。这种机制增强了 PT 细胞的白蛋白内吞作用，从而减少了白蛋白过载诱导的 TII 中的蛋白尿。这种作用不涉及 PT 白蛋白受体 megalin 的表达变化。此外，该途径的激活降低了 LLC-PK1 细胞（一种 PT 细胞系）在更高白蛋白浓度下诱导的细胞凋亡，与在病理生理条件下观察到的相似。我们的结果表明，锂治疗对白蛋白过载诱导的 TII 的保护作用涉及 mTORC2/PKB 途径的激活导致 PT 白蛋白内吞作用的增加。这些结果为理解锂对肾脏疾病进展的影响开辟了新的可能性。

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