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

Teixeira, D. E., Peruchetti, D. B., Silva, L. S., Silva-Aguiar, R. P., Oquendo, M. B., Silva-Filho, J. L. , Takiya, C. M., Leal-Cardoso, J. H., Pinheiro, A. A. S. and Caruso-Neves, C. (2019) Lithium ameliorates tubule-interstitial injury through activation of the mTORC2/protein kinase B pathway. PLoS ONE, 14(4), e0215871. (doi: 10.1371/journal.pone.0215871) (PMID:31002704) (PMCID: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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Da Silva Filho, Dr Joao

Creator Roles

Silva-Filho, J. L.: Investigation

• Authors: Teixeira, D. E., Peruchetti, D. B., Silva, L. S., Silva-Aguiar, R. P., Oquendo, M. B., Silva-Filho, J. L., Takiya, C. M., Leal-Cardoso, J. H., Pinheiro, A. A. S., and Caruso-Neves, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Copyright Holders: Copyright © 2019 Teixeira et al.
• First Published: First published in PLoS ONE 14(4): e0215871
• Publisher Policy: Reproduced under a Creative Commons License