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

Douglas E Teixeira,Christina M Takiya,Celso Caruso-Neves,Morgana B Oquendo,João Luiz Silva-Filho,Rodrigo P Silva-Aguiar,Leandro S Silva,Ana Acacia S Pinheiro,José Henrique Leal-Cardoso,Diogo B Peruchetti

doi:10.1371/journal.pone.0215871

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.

Highlights

Lithium salts have been used largely to treat mood disorders, including mania and depression [1,2]
Both the Bovine serum albumin (BSA)+lithium-treated group (LIT) and LIT groups presented higher water intake and urinary flow and decreased urinary creatinine levels compared with the control group (CONT) group
The BSA, BSA and lithium-treated group (BSA+LIT), and LIT groups showed an increased level of FENa+ compared with the CONT group, indicating modifications in tubular reabsorption

Summary

Introduction

Lithium salts have been used largely to treat mood disorders, including mania and depression [1,2]. Lithium ameliorates tubule-interstitial injury through activation of the mTORC2/PKB pathway and analysis, decision to publish, or preparation of the manuscript

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Conclusion