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

PLoS One 2019 19;14(4):e0215871. Epub 2019 Apr 19.

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

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.

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215871PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474631PMC
April 2019

Article Mentions


Provided by Crossref Event Data
twitter
Twitter:
April 23, 2019, 7:27 pm EST

Publication Analysis

Top Keywords

lithium treatment
16
induced albumin
16
tii induced
16
albumin overload
16
albumin endocytosis
16
albumin
10
progression renal
8
cells cell
8
llc-pk1 cells
8
renal disease
8
effects lithium
8
tubule-interstitial injury
8
treatment ameliorates
8
development tii
8
tii
7
lithium
7
induced
5
treatment tii
4
activation pathway
4
addition activation
4

Similar Publications