PMID- 31266025
OWN - NLM
STAT- MEDLINE
DCOM- 20200129
LR  - 20200703
IS  - 1423-0143 (Electronic)
IS  - 1420-4096 (Print)
IS  - 1420-4096 (Linking)
VI  - 44
IP  - 4
DP  - 2019
TI  - Rac1 GTPase Inhibition Blocked Podocyte Injury and Glomerular Sclerosis during 
      Hyperhomocysteinemia via Suppression of Nucleotide-Binding Oligomerization 
      Domain-Like Receptor Containing Pyrin Domain 3 Inflammasome Activation.
PG  - 513-532
LID - 10.1159/000500457 [doi]
AB  - Elevated homocysteine (Hcy) levels have been shown to activate nucleotide-binding 
      oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) 
      inflammasome leading to podocyte dysfunction and glomerular injury. However, it 
      remains unclear how this inflammasome activation in podocytes is a therapeutic 
      target for reversal of glomerular injury and ultimate sclerosis. The present 
      study tested whether inhibition of Rac1 GTPase activity suppresses NLRP3 
      inflammation activation and thereby blocks podocyte injury induced by elevated 
      Hcy. In cultured podocytes, we found that L-Hcy (the active Hcy form) stimulated 
      the NLRP3 inflammasome formation, as shown by increased colocalization of NLRP3 
      with apoptosis-associated speck-like protein (ASC) or caspase-1, which was 
      accompanied by increased interleukin-1beta production and caspase-1 activity, 
      indicating NLRP3 inflammasome activation. Rac1 activator, uridine triphosphate 
      (UTP), mimicked L-Hcy-induced NLRP3 inflammasome activation, while Rac1 inhibitor 
      NSC23766 blocked it. This Rac1 inhibition also prevented L-Hcy-induced podocyte 
      dysfunction. All these effects were shown to be mediated via lipid raft redox 
      signaling platforms with nicotinamide adenine dinucleotide phosphate oxidase 
      subunits and consequent O2- production. In animal studies, hyperhomocysteinemia 
      (hHcy) induced by folate-free diet was shown to induce NLRP3 inflammasome 
      formation and activation in glomeruli, which was also mimicked by UTP and 
      inhibited by NSC23766 to a comparable level seen in Nlrp3 gene knockout mice. 
      These results together suggest that Rac1 inhibition protects the kidney from 
      hHcy-induced podocyte injury and glomerular sclerosis due to its action to 
      suppress NLRP3 inflammasome activation in podocytes.
CI  - (c) 2019 The Author(s) Published by S. Karger AG, Basel.
FAU - Zhang, Qinghua
AU  - Zhang Q
AD  - Departments of Pharmacology and Toxicology, Virginia Commonwealth University, 
      Richmond, Virginia, USA.
FAU - Conley, Sabena M
AU  - Conley SM
AD  - Departments of Pharmacology and Toxicology, Virginia Commonwealth University, 
      Richmond, Virginia, USA.
FAU - Li, Guangbi
AU  - Li G
AD  - Departments of Pharmacology and Toxicology, Virginia Commonwealth University, 
      Richmond, Virginia, USA.
FAU - Yuan, Xinxu
AU  - Yuan X
AD  - Departments of Pharmacology and Toxicology, Virginia Commonwealth University, 
      Richmond, Virginia, USA.
FAU - Li, Pin-Lan
AU  - Li PL
AD  - Departments of Pharmacology and Toxicology, Virginia Commonwealth University, 
      Richmond, Virginia, USA, pin-lan.li@vcuhealth.org.
LA  - eng
GR  - R01 HL075316/HL/NHLBI NIH HHS/United States
GR  - R01 HL057244/HL/NHLBI NIH HHS/United States
GR  - R01 DK120491/DK/NIDDK NIH HHS/United States
GR  - R29 HL057244/HL/NHLBI NIH HHS/United States
GR  - R01 DK054927/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20190702
PL  - Switzerland
TA  - Kidney Blood Press Res
JT  - Kidney & blood pressure research
JID - 9610505
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Protective Agents)
RN  - 0 (RAC1 protein, human)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
RN  - EC 3.6.5.2 (rac1 GTP-Binding Protein)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Enzyme Inhibitors/pharmacology
MH  - GTP Phosphohydrolases/*antagonists & inhibitors
MH  - Humans
MH  - Hyperhomocysteinemia/complications/*metabolism
MH  - Inflammasomes/chemistry/drug effects/*metabolism
MH  - Kidney Glomerulus/*pathology
MH  - Mice
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
MH  - Podocytes/drug effects/*pathology
MH  - Protective Agents
MH  - Sclerosis/prevention & control
MH  - rac1 GTP-Binding Protein/antagonists & inhibitors
PMC - PMC6800118
MID - NIHMS1054409
OTO - NOTNLM
OT  - Glomerulosclerosis
OT  - Inflammatory machinery
OT  - Membrane rafts
OT  - Rac1 GTPase
OT  - Reactive oxygen species
COIS- Disclosure Statement The authors declare no conflicts of interest.
EDAT- 2019/07/03 06:00
MHDA- 2020/01/30 06:00
PMCR- 2020/07/02
CRDT- 2019/07/03 06:00
PHST- 2019/02/22 00:00 [received]
PHST- 2019/04/04 00:00 [accepted]
PHST- 2019/07/03 06:00 [pubmed]
PHST- 2020/01/30 06:00 [medline]
PHST- 2019/07/03 06:00 [entrez]
PHST- 2020/07/02 00:00 [pmc-release]
AID - 000500457 [pii]
AID - 10.1159/000500457 [doi]
PST - ppublish
SO  - Kidney Blood Press Res. 2019;44(4):513-532. doi: 10.1159/000500457. Epub 2019 Jul 
      2.