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Deletion of Rac1GTPase in the Myeloid Lineage Protects against
Inflammation-Mediated Kidney Injury in Mice
#MMPMID26939003
Nagase M
; Kurihara H
; Aiba A
; Young MJ
; Sakai T
PLoS One
2016[]; 11
(3
): e0150886
PMID26939003
show ga
Macrophage-mediated inflammation has been implicated in various kidney diseases.
We previously reported that Rac1, a Rho family small GTP-binding protein, was
overactivated in several chronic kidney disease models, and that Rac1 inhibitors
ameliorated renal injury, in part via inhibition of inflammation, but the
detailed mechanisms have not been clarified. In the present study, we examined
whether Rac1 in macrophages effects cytokine production and the inflammatory
mechanisms contributing to kidney derangement. Myeloid-selective Rac1 flox
control (M-Rac1 FC) and knockout (M-Rac1 KO) mice were generated using the
cre-loxP system. Renal function under basal conditions did not differ between
M-Rac1 FC and KO mice. Accordingly, lipopolysaccharide (LPS)-evoked kidney injury
model was created. LPS elevated blood urea nitrogen and serum creatinine,
enhanced expressions of kidney injury biomarkers, Kim-1 and Ngal, and promoted
tubular injury in M-Rac1 FC mice. By contrast, deletion of myeloid Rac1 almost
completely prevented the LPS-mediated renal impairment. LPS triggered a marked
induction of macrophage-derived inflammatory cytokines, IL-6 and TNF?, in M-Rac1
FC mice, which was accompanied by Rac1 activation, stimulation of reduced
nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, and reactive oxygen
species overproduction. These changes were inhibited in M-Rac1 KO mice. LPS
evoked F4/80-positive macrophages accumulation in the kidney, which was not
affected by myeloid Rac1 deficiency. We further tested the role of Rac1 signaling
in cytokine production using macrophage cell line, RAW264.7. Exposure to LPS
increased IL-6 and TNF? mRNA expression. The LPS-driven cytokine induction was
dose-dependently blocked by the Rac1 inhibitor EHT1864, NADPH oxidase inhibitor
diphenyleneiodonium, and NF-?B inhibitor BAY11-7082. In conclusion, genetic
ablation of Rac1 in the myeloid lineage protected against LPS-induced renal
inflammation and injury, by suppressing macrophage-derived cytokines, IL-6 and
TNF?, without blocking recruitment. Our data suggest that Rac1 in macrophage is a
novel target for the treatment of kidney disease through inhibition of cytokine
production.
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