High glucose reduces megalin-mediated albumin endocytosis in renal proximal tubule cells through protein kinase B O-GlcNAcylation

Peruchetti, Diogo B.; Silva-Aguiar, Rodrigo P.; Siqueira, Gabriela Marques; Dias, Wagner B.; Caruso-Neves, Celso

doi:10.1074/jbc.ra117.001337

Cited by 42 publications

(45 citation statements)

References 76 publications

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“…LLC-PK1 cells, a porcine PTEC line, were grown at 37 • C in 5% CO2 in low-glucose DMEM supplemented with 10% FBS and 1% penicillin/streptomycin (Caruso-Neves et al, 2005Lara et al, 2010;Lindoso et al, 2011;Peruchetti et al, 2011Peruchetti et al, , 2014Peruchetti et al, , 2018Peruchetti et al, , 2019Landgraf et al, 2014;Arnaud-Batista et al, 2016;Teixeira et al, 2019). After reach the confluence (85-90%), the serum-starved cells were treated with different compounds as indicated in the figure legends.…”

Section: Cell Culturementioning

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%

“…The rate of albumin endocytosis was assessed through the measurement of BSA-FITC uptake as described previously (Caruso-Neves et al, 2005;Peruchetti et al, 2018;Silva-Aguiar et al, 2018;Teixeira et al, 2019). Briefly, the cells were incubated with Ringer solution (12.4 mM HEPES-Tris (pH 7.4), 140 mM NaCl, 2.7 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 5 mM glucose) containing 30 µg/mL BSA-FITC at 37 • C for 30 min.…”

Section: Assessment Of Albumin Endocytosismentioning

confidence: 99%

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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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Section: Cell Culturementioning

confidence: 99%

Section: Immunoblottingmentioning

confidence: 99%

Section: Assessment Of Albumin Endocytosismentioning

confidence: 99%

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

et al. 2020

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“…The O‐GlcNAc modification of several key cell surface receptors is critical in the regulation of various physiological processes . For example, the O‐GlcNAc modification of AMPA receptor subunits GluA2 and GluA3 and Megalin is required for synaptic transmission and renal epithelial nutrient reabsorption, respectively. The degree of O‐GlcNAc modification also impacts focal adhesion formation mediated by integrins, the latter of which are predicted to be O‐GlcNAc modified .…”

Section: Direct Control Of Endocytic Membrane Traffic By Metabolitesmentioning

confidence: 99%

Energetic adaptations: Metabolic control of endocytic membrane traffic

Rahmani

Defferrari

Wakarchuk

et al. 2019

Traffic

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Endocytic membrane traffic controls the access of myriad cell surface proteins to the extracellular milieu, and thus gates nutrient uptake, ion homeostasis, signaling, adhesion and migration. Coordination of the regulation of endocytic membrane traffic with a cell's metabolic needs represents an important facet of maintenance of homeostasis under variable conditions of nutrient availability and metabolic demand. Many studies have revealed intimate regulation of endocytic membrane traffic by metabolic cues, from the specific control of certain receptors or transporters, to broader adaptation or remodeling of the endocytic membrane network. We examine how metabolic sensors such as AMP‐activated protein kinase, mechanistic target of rapamycin complex 1 and hypoxia inducible factor 1 determine sufficiency of various metabolites, and in turn modulate cellular functions that includes control of endocytic membrane traffic. We also examine how certain metabolites can directly control endocytic traffic proteins, such as the regulation of specific protein glycosylation by limiting levels of uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc) produced by the hexosamine biosynthetic pathway. From these ideas emerge a growing appreciation that endocytic membrane traffic is orchestrated by many intrinsic signals derived from cell metabolism, allowing alignment of the functions of cell surface proteins with cellular metabolic requirements. Endocytic membrane traffic determines how cells interact with their environment, thus defining many aspects of nutrient uptake and energy consumption. We examine how intrinsic signals that reflect metabolic status of a cell regulate endocytic traffic of specific proteins, and, in some cases, exert broad control of endocytic membrane traffic phenomena. Hence, endocytic traffic is versatile and adaptable and can be modulated to meet the changing metabolic requirements of a cell.

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“…This was of particular interest because it reflected the fact that all our study patients were nephrotic. In cell culture models, high glucose levels are known to reduce the megalin-mediated albumin endocytosis in renal proximal tubule cells [36]. Additionally, in renal proximal tubule cells, the inhibition of Akt is known to abrogate insulin-induced albumin endocytosis [37].…”

Section: Discussionmentioning

confidence: 99%

Urinary Exosomal MicroRNA Signatures in Nephrotic, Biopsy-Proven Diabetic Nephropathy

Lee

et al. 2020

JCM

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Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD). Elucidating the mechanisms underlying proteinuria in DKD is crucial because it is a common problem in DKD-related mortality and morbidity. MicroRNAs (miRs) associated with DKD have been detected in experimental diabetes models and in patients with both diabetes and CKD. Here, we aimed to investigate pathologic miRs in diabetic nephropathy (DN) by prospectively following six nephrotic, biopsy-proven isolated DN patients (enrolled between August 2015 and July 2017) for one year. The urinary exosomes were isolated at the time of the biopsy and the contained miRs were analyzed by next-generation sequencing. The results were compared to the control group, composed of age-, gender-, and CKD stage-matched patients with proteinuric CKD who did not present diabetes. Among the 72 identified miRs, we investigated eight (miR-188-5p, miR-150-3p, miR-760, miR-3677-3p, miR-548ah-3p, miR-548p, miR-320e, and miR-23c) exhibiting the strongest upregulation (13-15 fold) and two (miR-133a-3p and miR-153-3p) with the strongest downregulation (7-9 fold). The functional analysis of these miRs showed that they were involved in known and novel pathways of DN, supporting their pathologic roles. The bioinformatics-based prediction of the target genes of these miRs will inspire future research on the mechanisms underlying DN pathogenesis.

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High glucose reduces megalin-mediated albumin endocytosis in renal proximal tubule cells through protein kinase B O-GlcNAcylation

Cited by 42 publications

References 76 publications

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

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

Energetic adaptations: Metabolic control of endocytic membrane traffic

Urinary Exosomal MicroRNA Signatures in Nephrotic, Biopsy-Proven Diabetic Nephropathy

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