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

Date Published: April 19, 2019

Publisher: Public Library of Science

Author(s): Douglas E. Teixeira, Diogo B. Peruchetti, Leandro S. Silva, Rodrigo P. Silva-Aguiar, Morgana B. Oquendo, João Luiz Silva-Filho, Christina M. Takiya, José Henrique Leal-Cardoso, Ana Acacia S. Pinheiro, Celso Caruso-Neves, Niels Olsen Saraiva Câmara.


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.

Partial Text

Lithium salts have been used largely to treat mood disorders, including mania and depression [1,2]. However, this therapy is compromised due to induction of nephrotoxicity after long-term treatment in both animal models and human patients [1–5]. On the other hand, some reports showed that lithium treatment attenuated acute kidney injury (AKI) induced by gentamicin, cisplatin, lipopolysaccharide (LPS), and ischemia/reperfusion (IR) in animal models [6–8]. This protective effect of lithium was associated with action on the cortical tubular segments, indicating that lithium modulates proximal tubule (PT) function and tubule-interstitial injury (TII).

Despite the widespread use of lithium for the treatment of mood disorders, the renal effects are still controversial [2–8]. Some studies indicate that lithium treatment ameliorates AKI induced by LPS or IR, and this effect is correlated to injuries in cortical nephron segments [6–8]. We studied the effect of lithium treatment on TII induced by albumin overload. It was observed that development of TII was attenuated by lithium treatment. We are proposing that this effect involves modulation of PT albumin endocytosis and activation of the mTORC2/PKB pathway.




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