PMID- 31085234
OWN - NLM
STAT- MEDLINE
DCOM- 20200821
LR  - 20200901
IS  - 1873-3913 (Electronic)
IS  - 0898-6568 (Print)
IS  - 0898-6568 (Linking)
VI  - 61
DP  - 2019 Sep
TI  - Hydrogen sulphide mitigates homocysteine-induced apoptosis and matrix remodelling 
      in mesangial cells through Akt/FOXO1 signalling cascade.
PG  - 66-77
LID - S0898-6568(19)30101-9 [pii]
LID - 10.1016/j.cellsig.2019.05.003 [doi]
AB  - Cellular damage and accumulation of extracellular matrix (ECM) protein in the 
      glomerulo-interstitial space are the signatures of chronic kidney disease (CKD). 
      Hyperhomocysteinemia (HHcy), a high level of homocysteine (Hcy) is associated 
      with CKD and further contributes to kidney damage. Despite a large number of 
      studies, the signalling mechanism of Hcy-mediated cellular damage and ECM 
      remodelling in kidney remains inconclusive. Hcy metabolizes to produce hydrogen 
      sulphide (H(2)S), and a number of studies have shown that H(2)S mitigates the 
      adverse effect of HHcy in a variety of diseases involving several signalling 
      molecules, including forkhead box O (FOXO) protein. FOXO is a group of 
      transcription factor that includes FOXO1, which plays important roles in cell 
      growth and proliferation. On the other hand, a cell survival factor, Akt 
      regulates FOXO under normal condition. However, the involvement of Akt/FOXO1 
      pathway in Hcy-induced mesangial cell damage remains elusive, and whether H(2)S 
      plays any protective roles has yet to be clearly defined. We treated mouse 
      mesangial cells with or without H(2)S donor, GYY4137 and FOXO1 inhibitor, 
      AS1842856 in HHcy condition and determined the involvement of Akt/FOXO1 
      signalling cascades. Our results indicated that Hcy inactivated Akt and activated 
      FOXO1 by dephosphorylating both the signalling molecules and induced FOXO1 
      nuclear translocation followed by activation of the FOXO1 transcription factor. 
      These led to the induction of cellular apoptosis and synthesis of excessive ECM 
      protein, in part, due to increased ROS production, loss of mitochondrial membrane 
      potential (DeltaPsim), reduction in intracellular ATP concentration, increased MMP-2, 
      -9, -14 mRNA and protein expression, and Col I, IV and fibronectin protein 
      expression. Interestingly, GYY4137 or AS1842856 treatment prevented these changes 
      by modulating Akt/FOXO1 axis in HHcy. We conclude that GYY4137 and/or AS1842856 
      mitigates HHcy induced mesangial cell damage and ECM remodelling by regulating 
      Akt/FOXO1 pathway.
CI  - Copyright (c) 2019 Elsevier Inc. All rights reserved.
FAU - Majumder, Suravi
AU  - Majumder S
AD  - Department of Physiology, University of Louisville School of Medicine, 
      Louisville, KY, United States of America.
FAU - Ren, Lu
AU  - Ren L
AD  - Department of Pathology and Laboratory Medicine, Indiana University School of 
      Medicine, Indianapolis, IN, United States of America.
FAU - Pushpakumar, Sathnur
AU  - Pushpakumar S
AD  - Department of Physiology, University of Louisville School of Medicine, 
      Louisville, KY, United States of America.
FAU - Sen, Utpal
AU  - Sen U
AD  - Department of Physiology, University of Louisville School of Medicine, 
      Louisville, KY, United States of America. Electronic address: 
      u0sen001@louisville.edu.
LA  - eng
GR  - R01 DK104653/DK/NIDDK NIH HHS/United States
GR  - R01 DK116591/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 - 20190511
PL  - England
TA  - Cell Signal
JT  - Cellular signalling
JID - 8904683
RN  - 0 
      (5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic 
      acid)
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (Foxo1 protein, mouse)
RN  - 0 (GYY 4137)
RN  - 0 (Morpholines)
RN  - 0 (Organothiophosphorus Compounds)
RN  - 0 (Quinolones)
RN  - 0 (Reactive Oxygen Species)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - YY9FVM7NSN (Hydrogen Sulfide)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Cell Line
MH  - Extracellular Matrix/drug effects/*metabolism
MH  - Forkhead Box Protein O1/antagonists & inhibitors/*metabolism
MH  - Homocysteine/*pharmacology
MH  - Hydrogen Sulfide/*metabolism
MH  - Hyperhomocysteinemia/drug therapy
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mesangial Cells/*metabolism
MH  - Mice
MH  - Morpholines/pharmacology
MH  - Organothiophosphorus Compounds/pharmacology
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Quinolones/pharmacology
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction/drug effects
PMC - PMC6561819
MID - NIHMS1530174
OTO - NOTNLM
OT  - Caspase
OT  - Collagen
OT  - Fibronectin
OT  - GYY4137
OT  - Homocysteine
OT  - MMP
COIS- Disclosures The authors declare no conflicts of interest, financial or otherwise.
EDAT- 2019/05/16 06:00
MHDA- 2020/08/22 06:00
PMCR- 2020/09/01
CRDT- 2019/05/16 06:00
PHST- 2018/12/18 00:00 [received]
PHST- 2019/03/28 00:00 [revised]
PHST- 2019/05/02 00:00 [accepted]
PHST- 2019/05/16 06:00 [pubmed]
PHST- 2020/08/22 06:00 [medline]
PHST- 2019/05/16 06:00 [entrez]
PHST- 2020/09/01 00:00 [pmc-release]
AID - S0898-6568(19)30101-9 [pii]
AID - 10.1016/j.cellsig.2019.05.003 [doi]
PST - ppublish
SO  - Cell Signal. 2019 Sep;61:66-77. doi: 10.1016/j.cellsig.2019.05.003. Epub 2019 May 
      11.