PMID- 31601454
OWN - NLM
STAT- MEDLINE
DCOM- 20201104
LR  - 20201201
IS  - 1523-1755 (Electronic)
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 96
IP  - 6
DP  - 2019 Dec
TI  - Renal tubular cell spliced X-box binding protein 1 (Xbp1s) has a unique role in 
      sepsis-induced acute kidney injury and inflammation.
PG  - 1359-1373
LID - S0085-2538(19)30775-6 [pii]
LID - 10.1016/j.kint.2019.06.023 [doi]
AB  - 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.
CI  - Copyright (c) 2019 International Society of Nephrology. Published by Elsevier Inc. 
      All rights reserved.
FAU - Ferre, Silvia
AU  - Ferre S
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA; Charles and Jane Pak Center for Mineral Metabolism and 
      Clinical Research, University of Texas Southwestern Medical Center, Dallas, 
      Texas, USA. Electronic address: silvia.ferre@utsouthwestern.edu.
FAU - Deng, Yingfeng
AU  - Deng Y
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA; Touchstone Diabetes Center, University of Texas Southwestern 
      Medical Center, Dallas, Texas, USA.
FAU - Huen, Sarah C
AU  - Huen SC
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA; Department of Pharmacology, University of Texas Southwestern 
      Medical Center, Dallas, Texas, USA.
FAU - Lu, Christopher Y
AU  - Lu CY
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA.
FAU - Scherer, Philipp E
AU  - Scherer PE
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA; Touchstone Diabetes Center, University of Texas Southwestern 
      Medical Center, Dallas, Texas, USA.
FAU - Igarashi, Peter
AU  - Igarashi P
AD  - Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
FAU - Moe, Orson W
AU  - Moe OW
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA; Charles and Jane Pak Center for Mineral Metabolism and 
      Clinical Research, University of Texas Southwestern Medical Center, Dallas, 
      Texas, USA; Department of Physiology, University of Texas Southwestern Medical 
      Center, Dallas, Texas, USA. Electronic address: Orson.Moe@UTSouthwestern.edu.
LA  - eng
GR  - K08 DK110424/DK/NIDDK NIH HHS/United States
GR  - P01 DK088761/DK/NIDDK NIH HHS/United States
GR  - R01 DK091392/DK/NIDDK NIH HHS/United States
GR  - R01 DK096251/DK/NIDDK NIH HHS/United States
GR  - R01 DK099110/DK/NIDDK NIH HHS/United States
GR  - R01 DK055758/DK/NIDDK NIH HHS/United States
GR  - R37 DK042921/DK/NIDDK NIH HHS/United States
GR  - P01 AG051459/AG/NIA NIH HHS/United States
GR  - P30 DK079328/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190801
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Lipopolysaccharides)
RN  - 0 (X-Box Binding Protein 1)
RN  - 0 (Xbp1 protein, mouse)
SB  - IM
MH  - Acute Kidney Injury/*etiology/metabolism
MH  - Animals
MH  - Female
MH  - Kidney Tubules/metabolism
MH  - Lipopolysaccharides
MH  - Male
MH  - Mice
MH  - Random Allocation
MH  - Sepsis/*complications/metabolism
MH  - X-Box Binding Protein 1/genetics/*metabolism
PMC - PMC7286357
MID - NIHMS1544023
OTO - NOTNLM
OT  - AKI
OT  - ER stress
OT  - Inflammation
OT  - Sepsis
OT  - Xbp1s
EDAT- 2019/10/12 06:00
MHDA- 2020/11/05 06:00
PMCR- 2020/12/01
CRDT- 2019/10/12 06:00
PHST- 2018/12/03 00:00 [received]
PHST- 2019/06/04 00:00 [revised]
PHST- 2019/06/27 00:00 [accepted]
PHST- 2019/10/12 06:00 [pubmed]
PHST- 2020/11/05 06:00 [medline]
PHST- 2019/10/12 06:00 [entrez]
PHST- 2020/12/01 00:00 [pmc-release]
AID - S0085-2538(19)30775-6 [pii]
AID - 10.1016/j.kint.2019.06.023 [doi]
PST - ppublish
SO  - Kidney Int. 2019 Dec;96(6):1359-1373. doi: 10.1016/j.kint.2019.06.023. Epub 2019 
      Aug 1.