PMID- 34717894
OWN - NLM
STAT- MEDLINE
DCOM- 20220215
LR  - 20240326
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Print)
IS  - 0002-9440 (Linking)
VI  - 192
IP  - 1
DP  - 2022 Jan
TI  - Exosome Biogenesis and Lysosome Function Determine Podocyte Exosome Release and 
      Glomerular Inflammatory Response during Hyperhomocysteinemia.
PG  - 43-55
LID - S0002-9440(21)00443-0 [pii]
LID - 10.1016/j.ajpath.2021.10.005 [doi]
AB  - Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 
      (NLRP3) inflammasome activation in podocytes is reportedly associated with 
      enhanced release of exosomes containing NLRP3 inflammasome products from these 
      cells during hyperhomocysteinemia (hHcy). This study examined the possible role 
      of increased exosome secretion during podocyte NLRP3 inflammasome activation in 
      the glomerular inflammatory response. Whether exosome biogenesis and lysosome 
      function are involved in the regulation of exosome release from podocytes during 
      hHcy in mice and upon stimulation of homocysteine (Hcy) in podocytes was tested. 
      By nanoparticle tracking analysis, treatments of mice with amitriptyline (acid 
      sphingomyelinase inhibitor), GW4869 (exosome biogenesis inhibitor), and rapamycin 
      (lysosome function enhancer) were found to inhibit elevated urinary exosomes 
      during hHcy. By examining NLRP3 inflammasome activation in glomeruli during hHcy, 
      amitriptyline (but not GW4869 and rapamycin) was shown to have an inhibitory 
      effect. However, all treatments attenuated glomerular inflammation and injury 
      during hHcy. In cell studies, Hcy treatment stimulated exosome release from 
      podocytes, which was prevented by amitriptyline, GW4869, and rapamycin. 
      Structured illumination microscopy revealed that Hcy inhibited 
      lysosome-multivesicular body interactions in podocytes, which was prevented by 
      amitriptyline or rapamycin but not GW4869. Thus, the data from this study shows 
      that activation of exosome biogenesis and dysregulated lysosome function are 
      critically implicated in the enhancement of exosome release from podocytes 
      leading to glomerular inflammation and injury during hHcy.
CI  - Copyright (c) 2022 American Society for Investigative Pathology. Published by 
      Elsevier Inc. All rights reserved.
FAU - Huang, Dandan
AU  - Huang D
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, Richmond, Virginia.
FAU - Li, Guangbi
AU  - Li G
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, Richmond, Virginia.
FAU - Bhat, Owais M
AU  - Bhat OM
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, Richmond, Virginia.
FAU - Zou, Yao
AU  - Zou Y
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, Richmond, Virginia.
FAU - Li, Ningjun
AU  - Li N
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, Richmond, Virginia.
FAU - Ritter, Joseph K
AU  - Ritter JK
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, Richmond, Virginia.
FAU - Li, Pin-Lan
AU  - Li PL
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, Richmond, Virginia. Electronic address: 
      pin-lan.li@vcuhealth.org.
LA  - eng
GR  - R01 DK054927/DK/NIDDK NIH HHS/United States
GR  - R01 DK120491/DK/NIDDK NIH HHS/United States
GR  - R01 HL145163/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20211027
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - EC 3.1.4.- (acid sphingomyelinase-1)
RN  - EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
SB  - IM
MH  - Animals
MH  - Exosomes/*metabolism
MH  - Homocysteine/metabolism
MH  - Hyperhomocysteinemia/*pathology
MH  - Inflammasomes/metabolism
MH  - Inflammation/*pathology
MH  - Kidney Glomerulus/*pathology
MH  - Lysosomes/*metabolism
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Multivesicular Bodies/metabolism
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
MH  - Podocytes/*metabolism/pathology
MH  - Sphingomyelin Phosphodiesterase/metabolism
MH  - Mice
PMC - PMC8759037
EDAT- 2021/11/01 06:00
MHDA- 2022/02/16 06:00
PMCR- 2023/01/01
CRDT- 2021/10/31 20:45
PHST- 2021/08/31 00:00 [received]
PHST- 2021/10/04 00:00 [revised]
PHST- 2021/10/07 00:00 [accepted]
PHST- 2021/11/01 06:00 [pubmed]
PHST- 2022/02/16 06:00 [medline]
PHST- 2021/10/31 20:45 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - S0002-9440(21)00443-0 [pii]
AID - 10.1016/j.ajpath.2021.10.005 [doi]
PST - ppublish
SO  - Am J Pathol. 2022 Jan;192(1):43-55. doi: 10.1016/j.ajpath.2021.10.005. Epub 2021 
      Oct 27.