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.

Increasing evidence has highlighted the role of tubule-interstitial injury (TII) as a vital step in the pathogenesis of acute kidney injury (AKI). Incomplete repair of TII during AKI could lead to the development of chronic kidney disease. Changes in albumin endocytosis in proximal tubule epithelial cells (PTECs) is linked to the development of TII. In this context, interleukin (IL)-4 has been shown to be an important factor in modulating recovery of TII. We have studied the possible role of IL-4 in TII induced by albumin overload. A subclinical AKI model characterized by albumin overload in the proximal tubule was used, without changing glomerular function. Four groups were generated: (1) CONT, wild-type mice treated with saline; (2) BSA, wild-type mice treated with 10 g/kg/day bovine serum albumin (BSA); (3) KO, IL4Rα −/− mice treated with saline; and (4) KO + BSA, IL4Rα −/− mice treated with BSA. As reported previously, mice in the BSA group developed TII without changes in glomerular function. The following parameters were increased in the KO + BSA group compared with the BSA group: (1) tubular injury score; (2) urinary γ-glutamyltransferase; (3) CD4 + T cells, dendritic cells, macrophages, and neutrophils are associated with increases in renal IL-6, IL-17, and transforming growth factor β. A decrease in M2-subtype macrophages associated with a decrease in collagen deposition was observed. Using LLC-PK1 cells, a model of PTECs, we observed that (1) these cells express IL-4 receptor α chain associated with activation of the JAK3/STAT6 pathway; (2) IL-4 alone did not change albumin endocytosis but did reverse the inhibitory effect of higher albumin concentration. This effect was abolished by JAK3 inhibitor. A further increase in urinary protein and creatinine levels was observed in the KO + BSA group compared with the BSA group, but not compared with the CONT group. These observations indicate that IL-4 has a protective role in the development of TII induced by albumin overload that is correlated with modulation of the proinflammatory response. We propose that megalin-mediated albumin endocytosis in PTECs could work as a sensor, transducer, and target during the genesis of TII.

Background: Plasmodium falciparum , the etiologic agent of malaria, is a major cause of infant death in Africa. Although research on the contact system has been revitalized by recent discoveries in the field of thrombosis, limited efforts were done to investigate the role of its proinflammatory arm, the kallikrein kinin system (KKS), in the pathogenesis of neglected parasitic diseases, such as malaria. Owing to the lack of animal models, the dynamics of central nervous system (CNS) pathology caused by the sequestration of erythrocytic stages of P. falciparum is not fully understood. Given the precedent that kinins destabilize the blood brain barrier (BBB) in ischemic stroke, here we sought to determine whether Plasmodium falciparum infected erythrocytes ( Pf -iRBC) conditioned medium enhances parasite sequestration and impairs BBB integrity via activation of the kallikrein kinin system (KKS). Methods: Monolayers of human brain endothelial cell line (BMECs) are preincubated with the conditioned medium from Pf -iRBCs or RBCs (controls) in the presence or absence of HOE-140 or DALBK, antagonists of bradykinin receptor B2 (B2R) and bradykinin receptor B1 (B1R), respectively. Following washing, the treated monolayers are incubated with erythrocytes, infected or not with P. falciparum mature forms, to examine whether the above treatment (i) has impact on the adhesion of Pf -iRBC to BMEC monolayer, (ii) increases the macromolecular permeability of the tracer BSA-FITC, and (iii) modifies the staining pattern of junctional proteins (ZO-1 and β-catenin). Results: We found that kinins generated in the parasite conditioned medium, acting via bradykinin B2 and/or B1 receptors (i) enhanced Pf -iRBC adhesion to the endothelium monolayer and (ii) impaired the endothelial junctions formed by ZO-1 and β-catenin, consequently disrupting the integrity of the BBB. Conclusions: Our studies raise the possibility that therapeutic targeting of kinin forming enzymes and/or endothelial bradykinin receptors might reduce extent of Pf -iRBC sequestration and help to preserve BBB integrity in cerebral malaria (CM).

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