Group V Secretory Phospholipase A2 Is Involved in Tubular Integrity and Sodium Handling in the Kidney

Silva-Filho, João Luiz; Peruchetti, Diogo B.; Moraes-Santos, Felipe; Landgraf, Sharon Schilling; Silva, Leandro Souza; Sirtoli, Gabriela Modenesi; Zamith-Miranda, Daniel; Takiya, Christina Maeda; Pinheiro, Ana Acácia S.; Diaz, Bruno L.; Caruso-Neves, Celso

doi:10.1371/journal.pone.0147785

Cited by 10 publications

(7 citation statements)

References 57 publications

(85 reference statements)

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“…Analysis of renal function was performed as described previously [22,30–32]. Briefly, the 24-h urine was collected to determine urinary flow (μL/min).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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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.

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“…Analysis of renal function was performed as described previously [22,30–32]. Briefly, the 24-h urine was collected to determine urinary flow (μL/min).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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“…The renal function parameters were obtained as previously published (Portella et al, 2013;Abreu et al, 2014;Landgraf et al, 2014;Silva-Filho et al, 2016;Silva-Aguiar et al, 2018;Teixeira et al, 2019). Urine samples were used to assess the levels of γ-glutamyltransferase (γ-GT) activity, proteins and creatinine using commercial kits, according to the manufacturer's instructions.…”

Section: Renal Function Analysismentioning

confidence: 99%

“…Immunoblotting was performed as described previously (Caruso-Neves et al, 2006;Lara et al, 2008;Peruchetti et al, 2011Peruchetti et al, , 2014Peruchetti et al, , 2018Landgraf et al, 2014;Arnaud-Batista et al, 2016;Silva-Filho et al, 2016;Ribeiro et al, 2018;Silva-Aguiar et al, 2018;Teixeira et al, 2019). Briefly, protein samples were obtained from LLC-PK1 cell lysate or renal cortex homogenate.…”

Section: Immunoblottingmentioning

confidence: 99%

IL-4 Receptor α Chain Protects the Kidney Against Tubule-Interstitial Injury Induced by Albumin Overload

et al. 2020

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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.

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“…To assess tissue collagen deposition, 7-μm-thick sections were prepared and stained with Picrosirius red stain (Sigma-Aldrich, St. Louis, MA). Images were obtained using a Nikon 80i eclipse microscope (Nikon, Japan) and the analysis and quantification were performed using Image-Pro Plus image analysis software (Media Cybernetics, Inc., USA) in at least 15 randomly captured photomicrographs [ 24 , 27 – 30 ].…”

Section: Methodsmentioning

confidence: 99%

“…The kidneys were removed and homogenized in a cold solution containing 10 mM HEPES-Tris (pH 7.6), 250 mM sucrose, 2 mM EDTA, and 1 mM phenylmethylsulfonyl fluoride. Homogenates were centrifuged at 7000 × g at 4°C for 10 min, and the final supernatant was stored at –80°C [ 27 , 28 , 30 ]. Total protein concentrations were determined by the Folin phenol method [ 31 ].…”

Section: Methodsmentioning

confidence: 99%

The angiotensin II/AT1 receptor pathway mediates malaria-induced acute kidney injury

et al. 2018

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Malaria-induced acute kidney injury (MAKI) is a life-threatening complication of severe malaria. Here, we investigated the potential role of the angiotensin II (Ang II)/AT1 receptor pathway in the development of MAKI. We used C57BL/6 mice infected by Plasmodium berghei ANKA (PbA-infected mice), a well-known murine model of severe malaria. The animals were treated with 20 mg/kg/day losartan, an antagonist of AT1 receptor, or captopril, an angiotensin-converting enzyme inhibitor. We observed an increase in the levels of plasma creatinine and blood urea nitrogen associated with a significant decrease in creatinine clearance, a marker of glomerular flow rate, and glomerular hypercellularity, indicating glomerular injury. PbA-infected mice also presented proteinuria and a high level of urinary γ-glutamyltransferase activity associated with an increase in collagen deposition and interstitial space, showing tubule-interstitial injury. PbA-infected mice were also found to have increased fractional excretion of sodium (FENa+) coupled with decreased cortical (Na++K+)ATPase activity. These injuries were associated with an increase in pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-6, interleukin-17, and interferon gamma, in the renal cortex of PbA-infected mice. All modifications of these structural, biochemical, and functional parameters observed in PbA-infected mice were avoided with simultaneous treatment with losartan or captopril. Our data allow us to postulate that the Ang II/AT1 receptor pathway mediates an increase in renal pro-inflammatory cytokines, which in turn leads to the glomerular and tubular injuries observed in MAKI.

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Group V Secretory Phospholipase A2 Is Involved in Tubular Integrity and Sodium Handling in the Kidney

Cited by 10 publications

References 57 publications

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

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

IL-4 Receptor α Chain Protects the Kidney Against Tubule-Interstitial Injury Induced by Albumin Overload

The angiotensin II/AT1 receptor pathway mediates malaria-induced acute kidney injury

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