Cellular antioxidant mechanisms control immunoglobulin light chain-mediated proximal tubule injury.

Antioxidants Catalase Hydrogen Peroxide Immunoglobulin Light Chains Kidney Tubules, Proximal
Catalase FoxO3a HMGB1 Hydrogen peroxide Protein kinase B STAT1 Sirtuin 1

Journal

Free radical biology & medicine
ISSN: 1873-4596
Titre abrégé: Free Radic Biol Med
Pays: United States
ID NLM: 8709159

Informations de publication

Date de publication:
01 08 2021
Historique:
received: 18 03 2021
revised: 27 04 2021
accepted: 06 05 2021
pubmed: 15 5 2021
medline: 29 6 2021
entrez: 14 5 2021
Statut: ppublish

Résumé

A major cause of morbidity and mortality in multiple myeloma is kidney injury from overproduction of monoclonal immunoglobulin light chains (FLC). FLC can induce damage through the production of hydrogen peroxide, which activates pro-inflammatory and pro-apoptotic pathways. The present study focused on catalase, a highly conserved antioxidant enzyme that degrades hydrogen peroxide. Initial findings were that FLC increased hydrogen peroxide levels but also decreased catalase levels and activity in proximal tubule epithelium. In order to clarify, we showed that the phosphatidylinositol 3-kinase inhibitor, LY294002, inhibited FLC-induced Akt-mediated deactivation of Forkhead box O class 3a (FoxO3a) and increased catalase activity in proximal tubule cells. Augmented catalase activity decreased FLC-mediated production of hydrogen peroxide as well as the associated increase in High Mobility Group Box 1 (HMGB1) protein release and caspase-3 activity. Coincubation of cells with FLC and an allosteric activator of Sirtuin 1 (SIRT1) was also sufficient to increase catalase activity and promote similar cytoprotective effects. Our studies confirmed that the mechanism of downregulation of catalase by FLC involved deactivation of FoxO3a and inhibition of SIRT1. Mechanistic understanding of catalase regulation allows for future treatments that target pathways that increase catalase in the setting of proximal tubule injury from FLC.

Identifiants

DOI: 10.1016/j.freeradbiomed.2021.05.011 PMID: 33989758 PMC: PMC8217262
pubmed: 33989758
pii: S0891-5849(21)00292-6
doi: 10.1016/j.freeradbiomed.2021.05.011
pmc: PMC8217262
mid: NIHMS1703470
pii:
doi:

Substances chimiques

Antioxidants 0
Immunoglobulin Light Chains 0
Hydrogen Peroxide BBX060AN9V
Catalase EC 1.11.1.6

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

80-90

Subventions

Organisme : CSRD VA
ID : I01 CX001326
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK079337
Pays : United States

Informations de copyright

Copyright © 2021 Elsevier Inc. All rights reserved.

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Auteurs

Kai Er Ying (KE)

Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA.

Wenguang Feng (W)

Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA.

Wei-Zhong Ying (WZ)

Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA.

Paul W Sanders (PW)

Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA; Department of Veterans Affairs Medical Center, Birmingham, AL, 35233, USA. Electronic address: psanders@uab.edu.

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Agents protecteurs › Antioxydants › Cellular antioxidant mechanisms control...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Peroxidases › Catalase › Cellular antioxidant mechanisms control...
questionsmedicales.fr › Composés chimiques organiques › Radicaux libres › Peroxydes › Peroxyde d'hydrogène › Cellular antioxidant mechanisms control...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Sous-unités des immunoglobulines › Chaines légères des immunoglobulines › Cellular antioxidant mechanisms control...
questionsmedicales.fr › Appareil urogénital › Voies urinaires › Rein › Néphrons › Tubules rénaux › Tubules contournés proximaux › Cellular antioxidant mechanisms control...