PMID- 33862145
OWN - NLM
STAT- MEDLINE
DCOM- 20210910
LR  - 20220716
IS  - 1879-260X (Electronic)
IS  - 0925-4439 (Print)
IS  - 0925-4439 (Linking)
VI  - 1867
IP  - 7
DP  - 2021 Jul 1
TI  - Contribution of podocyte inflammatory exosome release to glomerular inflammation 
      and sclerosis during hyperhomocysteinemia.
PG  - 166146
LID - S0925-4439(21)00079-X [pii]
LID - 10.1016/j.bbadis.2021.166146 [doi]
AB  - The nucleotide-binding oligomerization domain-like receptor containing pyrin 
      domain 3 (NLRP3) inflammasome has been implicated in podocyte injury and 
      glomerular sclerosis in response to hyperhomocysteinemia (hHcy). However, it 
      remains unknown how the products of NLRP3 inflammasome in cytoplasm are secreted 
      out of podocytes. In the present study, we tested whether exosome release serves 
      as a critical mechanism to mediate the action of NLRP3 inflammasome activation in 
      hHcy-induced glomerular injury. By various approaches, we found that hHcy induced 
      NLRP3 inflammasome activation and neutrophil infiltration in glomeruli of WT/WT 
      mice. Lysosome-MVB interaction in glomeruli remarkably decreased in WT/WT mice 
      fed with FF diet, leading to elevation of urinary exosome excretion of these 
      mice. Podocyte-derived exosomes containing pro-inflammatory cytokines increased 
      in urine of WT/WT mice in response to hHcy. The release of inflammatory exosomes 
      from podocytes was prevented by Smpd1 gene deletion but enhanced by 
      podocyte-specific Smpd1 gene overexpression (Smpd1 encodes Asm in mice). 
      Pathologically, hHcy-induced podocyte injury and glomerular sclerosis were 
      blocked by Smpd1 gene knockout but amplified by podocyte-specific Smpd1 gene 
      overexpression. Taken together, our results suggest that Asm-ceramide signaling 
      pathway contributes to NLRP3 inflammasome activation and robust release of 
      inflammatory exosomes in podocytes during hHcy, which together trigger local 
      glomerular inflammation and sclerosis.
CI  - Copyright (c) 2021 Elsevier B.V. All rights reserved.
FAU - Huang, Dandan
AU  - Huang D
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, Richmond, VA, USA.
FAU - Li, Guangbi
AU  - Li G
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, Richmond, VA, USA.
FAU - Zhang, Qinghua
AU  - Zhang Q
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, Richmond, VA, USA.
FAU - Bhat, Owais M
AU  - Bhat OM
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, Richmond, VA, USA.
FAU - Zou, Yao
AU  - Zou Y
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, Richmond, VA, USA.
FAU - Ritter, Joseph K
AU  - Ritter JK
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, Richmond, VA, USA.
FAU - Li, Pin-Lan
AU  - Li PL
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, Richmond, VA, USA. 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
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20210414
PL  - Netherlands
TA  - Biochim Biophys Acta Mol Basis Dis
JT  - Biochimica et biophysica acta. Molecular basis of disease
JID - 101731730
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - EC 3.1.4.12 (ASMase, mouse)
RN  - EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
SB  - IM
MH  - Animals
MH  - Exosomes/metabolism/*pathology
MH  - Hyperhomocysteinemia/*complications
MH  - Inflammasomes
MH  - Inflammation/etiology/metabolism/*pathology
MH  - Kidney Diseases/etiology/metabolism/*pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
MH  - Podocytes/metabolism/*pathology
MH  - Sclerosis/etiology/metabolism/*pathology
MH  - Sphingomyelin Phosphodiesterase/*physiology
PMC - PMC8122080
MID - NIHMS1695059
OTO - NOTNLM
OT  - Acid sphingomyelinase
OT  - Exosome
OT  - Glomerular inflammation
OT  - Hyperhomocysteinemia
OT  - NLRP3 inflammasome
OT  - Podocyte
COIS- Declaration of interest statement None of the authors have conflict of interest.
EDAT- 2021/04/17 06:00
MHDA- 2021/09/11 06:00
PMCR- 2022/07/01
CRDT- 2021/04/16 20:12
PHST- 2020/12/09 00:00 [received]
PHST- 2021/03/31 00:00 [revised]
PHST- 2021/04/05 00:00 [accepted]
PHST- 2021/04/17 06:00 [pubmed]
PHST- 2021/09/11 06:00 [medline]
PHST- 2021/04/16 20:12 [entrez]
PHST- 2022/07/01 00:00 [pmc-release]
AID - S0925-4439(21)00079-X [pii]
AID - 10.1016/j.bbadis.2021.166146 [doi]
PST - ppublish
SO  - Biochim Biophys Acta Mol Basis Dis. 2021 Jul 1;1867(7):166146. doi: 
      10.1016/j.bbadis.2021.166146. Epub 2021 Apr 14.