Renal tubular cell spliced X-box binding protein 1 (Xbp1s) has a unique role in sepsis-induced acute kidney injury and inflammation

Silvia Ferrè, Yingfeng Deng, Sarah C. Huen, Christopher Y. Lu, Philipp E. Scherer, Peter Igarashi, Orson W. Moe

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Sepsis is a systemic inflammatory state in response to infection, and concomitant acute kidney injury (AKI) increases mortality significantly. Endoplasmic reticulum stress is activated in many cell types upon microbial infection and modulates inflammation. The role of endoplasmic reticulum signaling in the kidney during septic AKI is unknown. Here we tested the role of the spliced X-box binding protein 1 (Xbp1s), a key component of the endoplasmic reticulum stress-activated pathways, in the renal response to sepsis in the lipopolysaccharide (LPS) model. Xbp1s was increased in the kidneys of mice treated with LPS but not in other models of AKI, or several chronic kidney disease models. The functional significance of Xbp1s induction was examined by genetic manipulation in renal tubules. Renal tubule-specific overexpression of Xbp1s caused severe tubule dilation and vacuolation with expression of the injury markers Kim1 and Ngal, the pro-inflammatory molecules interleukin-6 (Il6) and Toll-like receptor 4 (Tlr4), decreased kidney function and 50% mortality in five days. Renal tubule-specific genetic ablation of Xbp1 had no phenotype at baseline. However, after LPS, Xbp1 knockdown mice displayed lower renal NGAL, pro-apoptotic factor CHOP, serum creatinine levels, and a tendency towards lower Tlr4 compared to LPS-treated mice with intact Xbp1s. LPS treatment in Xbp1s-overexpressing mice caused a mild increase in NGAL and CHOP compared to LPS-treated mice without genetic Xbp1s overexpression. Thus, increased Xbp1s signaling in renal tubules is unique to sepsis-induced AKI and contributes to renal inflammation and injury. Inhibition of this pathway may be a potential portal to alleviate injury.

Original languageEnglish (US)
Pages (from-to)1359-1373
Number of pages15
JournalKidney international
Volume96
Issue number6
DOIs
StatePublished - Dec 2019

Bibliographical note

Funding Information:
SF was supported by the Ben J. Lipps Research Fellowship Program of the American Society of Nephrology Foundation for Kidney Research and the Charles and Jane Pak Center for Mineral Metabolism and Clinical Research Innovative Research Support Award. Work from the authors’ laboratories is supported by the National Institutes of Health (NIH) grants R01-DK091392 and R01-DK091392 (to OWM); NIH grants R01-DK55758 , R01-DK099110 , P01-DK088761 , and P01-AG051459 (to PES); NIH grant R37DK042921 (to PI); NIH grant K08-DK110424 and ASN Carl W. Gottschalk Research Scholar Grant (to SCH); and NIH grant R01-DK096251 (to CYL). We thank the University of Texas Southwestern Medical Center O’Brien Kidney Research Core Center (grant P30-DK079328 to OWM). We thank the University of Texas Southwestern Medical Center Metabolic Phenotyping Core for all creatinine and blood urea nitrogen measurements, Laurie H. Glimcher (Weill Cornell Medical College) for providing Xbp1s-Flox mice, Vishal D. Patel (University of Texas Southwestern Medical Center) for providing Ksp/ Cre ; Pkd1 F/F and Pkhd1/ Cre ; Pkd2 F/F mouse kidney samples, and Alexandru Bobulescu (University of Texas Southwestern Medical Center) for providing ob/ob mouse kidney samples. We thank Keng-Mean Lin and Matanel Yheskel (University of Texas Southwestern Medical Center) for excellent technical assistance and helpful discussion during the preparation of this manuscript.

Funding Information:
SF was supported by the Ben J. Lipps Research Fellowship Program of the American Society of Nephrology Foundation for Kidney Research and the Charles and Jane Pak Center for Mineral Metabolism and Clinical Research Innovative Research Support Award. Work from the authors? laboratories is supported by the National Institutes of Health (NIH) grants R01-DK091392 and R01-DK091392 (to OWM); NIH grants R01-DK55758, R01-DK099110, P01-DK088761, and P01-AG051459 (to PES); NIH grant R37DK042921 (to PI); NIH grant K08-DK110424 and ASN Carl W. Gottschalk Research Scholar Grant (to SCH); and NIH grant R01-DK096251 (to CYL). We thank the University of Texas Southwestern Medical Center O'Brien Kidney Research Core Center (grant P30-DK079328 to OWM). We thank the University of Texas Southwestern Medical Center Metabolic Phenotyping Core for all creatinine and blood urea nitrogen measurements, Laurie H. Glimcher (Weill Cornell Medical College) for providing Xbp1s-Flox mice, Vishal D. Patel (University of Texas Southwestern Medical Center) for providing Ksp/Cre;Pkd1F/F and Pkhd1/Cre;Pkd2F/F mouse kidney samples, and Alexandru Bobulescu (University of Texas Southwestern Medical Center) for providing ob/ob mouse kidney samples. We thank Keng-Mean Lin and Matanel Yheskel (University of Texas Southwestern Medical Center) for excellent technical assistance and helpful discussion during the preparation of this manuscript.

Publisher Copyright:
© 2019 International Society of Nephrology

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

  • AKI
  • ER stress
  • Inflammation
  • Sepsis
  • Xbp1s

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