PMID- 38411015
OWN - NLM
STAT- MEDLINE
DCOM- 20240313
LR  - 20240416
IS  - 1470-8736 (Electronic)
IS  - 0143-5221 (Linking)
VI  - 138
IP  - 6
DP  - 2024 Mar 20
TI  - Enhanced STAT3/PIK3R1/mTOR signaling triggers tubular cell inflammation and 
      apoptosis in septic-induced acute kidney injury: implications for therapeutic 
      intervention.
PG  - 351-369
LID - 10.1042/CS20240059 [doi]
AB  - Septic acute kidney injury (AKI) is a severe form of renal dysfunction associated 
      with high morbidity and mortality rates. However, the pathophysiological 
      mechanisms underlying septic AKI remain incompletely understood. Herein, we 
      investigated the signaling pathways involved in septic AKI using the mouse models 
      of lipopolysaccharide (LPS) treatment and cecal ligation and puncture (CLP). In 
      these models, renal inflammation and tubular cell apoptosis were accompanied by 
      the aberrant activation of the mechanistic target of rapamycin (mTOR) and the 
      signal transducer and activator of transcription 3 (STAT3) signaling pathways. 
      Pharmacological inhibition of either mTOR or STAT3 significantly improved renal 
      function and reduced apoptosis and inflammation. Interestingly, inhibition of 
      STAT3 with pharmacological inhibitors or small interfering RNA blocked 
      LPS-induced mTOR activation in renal tubular cells, indicating a role of STAT3 in 
      mTOR activation. Moreover, knockdown of STAT3 reduced the expression of the 
      phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1/p85alpha), a key subunit of 
      the phosphatidylinositol 3-kinase for AKT and mTOR activation. Chromatin 
      immunoprecipitation assay also proved the binding of STAT3 to PIK3R1 gene 
      promoter in LPS-treated kidney tubular cells. In addition, knockdown of PIK3R1 
      suppressed mTOR activation during LPS treatment. These findings highlight the 
      dysregulation of mTOR and STAT3 pathways as critical mechanisms underlying the 
      inflammatory and apoptotic phenotypes observed in renal tubular cells during 
      septic AKI, suggesting the STAT3/ PIK3R1/mTOR pathway as a therapeutic target of 
      septic AKI.
CI  - (c) 2024 The Author(s). Published by Portland Press Limited on behalf of the 
      Biochemical Society.
FAU - Fu, Ying
AU  - Fu Y
AD  - Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood 
      Purification, The Second Xiangya Hospital of Central South University, Changsha 
      410011, China.
FAU - Xiang, Yu
AU  - Xiang Y
AD  - Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood 
      Purification, The Second Xiangya Hospital of Central South University, Changsha 
      410011, China.
FAU - Zha, Jie
AU  - Zha J
AD  - Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood 
      Purification, The Second Xiangya Hospital of Central South University, Changsha 
      410011, China.
FAU - Chen, Guochun
AU  - Chen G
AD  - Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood 
      Purification, The Second Xiangya Hospital of Central South University, Changsha 
      410011, China.
FAU - Dong, Zheng
AU  - Dong Z
AUID- ORCID: 0000-0003-3538-8095
AD  - Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood 
      Purification, The Second Xiangya Hospital of Central South University, Changsha 
      410011, China.
AD  - Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta 
      University and Charlie Norwood VA Medical Center, Augusta, GA, U.S.A.
LA  - eng
GR  - 82090024/National Natural Science Foundation of China (NSFC)/
GR  - 82170759/National Natural Science Foundation of China (NSFC)/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Clin Sci (Lond)
JT  - Clinical science (London, England : 1979)
JID - 7905731
RN  - 0 (Lipopolysaccharides)
RN  - W36ZG6FT64 (Sirolimus)
RN  - 0 (STAT3 Transcription Factor)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.1.137 (Pik3r1 protein, mouse)
RN  - EC 2.7.1.137 (Class Ia Phosphatidylinositol 3-Kinase)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Acute Kidney Injury/metabolism
MH  - Apoptosis
MH  - Inflammation/metabolism
MH  - Kidney/metabolism
MH  - Lipopolysaccharides
MH  - *Sepsis/complications/metabolism
MH  - Sirolimus/therapeutic use
MH  - STAT3 Transcription Factor/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Class Ia Phosphatidylinositol 3-Kinase/metabolism
OTO - NOTNLM
OT  - Acute kidney injury
OT  - STAT3
OT  - apoptosis
OT  - inflammation
OT  - mTOR
OT  - sepsis
EDAT- 2024/02/27 06:45
MHDA- 2024/03/13 06:46
CRDT- 2024/02/27 05:43
PHST- 2024/01/10 00:00 [received]
PHST- 2024/02/20 00:00 [revised]
PHST- 2024/02/26 00:00 [accepted]
PHST- 2024/03/13 06:46 [medline]
PHST- 2024/02/27 06:45 [pubmed]
PHST- 2024/02/27 05:43 [entrez]
AID - 234105 [pii]
AID - 10.1042/CS20240059 [doi]
PST - ppublish
SO  - Clin Sci (Lond). 2024 Mar 20;138(6):351-369. doi: 10.1042/CS20240059.