O-GlcNAcylation reduces proximal tubule protein reabsorption and promotes proteinuria in spontaneously hypertensive rats

Silva-Aguiar, Rodrigo P.; Bezerra, Nathalia Cristina Ferreira; Lucena, Miguel C.; Sirtoli, Gabriela Modenesi; Sudo, Roberto T.; Zapata‐Sudo, Gisele; Takiya, Christina Maeda; Pinheiro, Ana Acácia S.; Dias, Wagner B.; Caruso-Neves, Celso

doi:10.1074/jbc.ra118.001746

Cited by 45 publications

(48 citation statements)

References 47 publications

(39 reference statements)

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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%

“…After blockade of non-specific binding, the membranes were incubated with specific primary antibodies and their respective HRP-conjugated IgG secondary antibodies, according to the manufacturer's instructions. ECL Prime was used to detect the proteins of interest Ribeiro et al, 2018;Silva-Aguiar et al, 2018;Teixeira et al, 2019). All the images were obtained using the Image Quant LAS4000 Image processing system (GE Healthcare Life Sciences, Pittsburgh, PA, United States) and processed by adjusting the brightness and contrast using NIH ImageJ software (version 1.6.0).…”

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: Renal Function Analysismentioning

confidence: 99%

Section: Immunoblottingmentioning

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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T‐2 Toxin‐Mediated β‐Arrestin‐1 O‐GlcNAcylation Exacerbates Glomerular Podocyte Injury via Regulating Histone Acetylation

Li,

Sun,

Zhu

et al. 2023

Advanced Science

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T‐2 toxin causes renal dysfunction with proteinuria and glomerular podocyte damage. This work explores the role of metabolic disorder/reprogramming‐mediated epigenetic modification in the progression of T‐2 toxin‐stimulated podocyte injury. A metabolomics experiment is performed to assess metabolic responses to T‐2 toxin infection in human podocytes. Roles of protein O‐linked‐N‐acetylglucosaminylation (O‐GlcNAcylation) in regulating T‐2 toxin‐stimulated podocyte injury in mouse and podocyte models are assessed. O‐GlcNAc target proteins are recognized by mass spectrometry and co‐immunoprecipitation experiments. Moreover, histone acetylation and autophagy levels are measured. T‐2 toxin infection upregulates glucose transporter type 1 (GLUT1) expression and enhances hexosamine biosynthetic pathway in glomerular podocytes, resulting in a significant increase in β‐arrestin‐1 O‐GlcNAcylation. Decreasing β‐arrestin‐1 or O‐GlcNAc transferase (OGT) effectively prevents T‐2 toxin‐induced renal dysfunction and podocyte injury. Mechanistically, O‐GlcNAcylation of β‐arrestin‐1 stabilizes β‐arrestin‐1 to activate the mammalian target of rapamycin (mTOR) pathway as well as to inhibit autophagy during podocyte injury by promoting H4K16 acetylation. To sum up, OGT‐mediated β‐arrestin‐1 O‐GlcNAcylation is a vital regulator in the development of T‐2 toxin‐stimulated podocyte injury via activating the mTOR pathway to suppress autophagy. Targeting β‐arrestin‐1 or OGT can be a potential therapy for T‐2 toxin infection‐associated glomerular injury, especially podocyte injury.

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O-GlcNAcylation reduces proximal tubule protein reabsorption and promotes proteinuria in spontaneously hypertensive rats

Cited by 45 publications

References 47 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

T‐2 Toxin‐Mediated β‐Arrestin‐1 O‐GlcNAcylation Exacerbates Glomerular Podocyte Injury via Regulating Histone Acetylation

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