Propofol ameliorates renal ischemia/reperfusion injury by enhancing macrophage M2 polarization through PPARγ/STAT3 signaling

Abstract

Propofol (Pro) confers protection against renal ischemia/reperfusion (rI/R) injury through incompletely characterized mechanisms. Since Pro has shown net anti-inflammatory properties as part of its beneficial effects, we examined the potential role of Pro in the modulation of macrophage polarization status during both rI/R injury in vivo and exposure of cultured peritoneal macrophages (PMs) to hypoxia/reoxygenation (H/R). Rats were subjected to 45-min r/IR surgery or a sham procedure and administered PBS (vehicle) or Pro during the ischemia stage. Pro administration attenuated rI/R-induced kidney damage and renal TNF-α, IL-6, and CXCL-10 expression. Enhanced macrophage M2 polarization, evidenced by reduced iNOS and increased Arg1 and Mrc1 mRNA levels, was further detected after Pro treatment both in the kidney, after rI/R in vivo, and in H/R-treated PMs. Pro administration also repressed phosphorylated signal transducer and activator of transcription 1 (p-STAT1) and increased p-STAT3, p-STAT6, and peroxisome proliferatoractivated receptor-γ (PPARγ) mRNA levels in H/R-exposed PMs. Importantly, siRNA-mediated PPARγ silencing repressed Pro-mediated STAT3 activation in PMs and restored proinflammatory cytokine levels and prevented macrophage M2 marker expression in both rI/R-treated rats and cultured PMs. These findings suggest that Pro confers renoprotection against rI/R by stimulating PPARγ/STAT3-dependent macrophage conversion to the M2 phenotype.

GPX3 and GSTT1 as biomarkers related to oxidative stress during renal ischemia reperfusion injuries and their relationship with immune infiltration

“…Many studies have confirmed the effect of drugs or molecular compounds on kidney IRIs. For example, propofol can enhance the polarization of macrophage M2 through the PPARγ/STAT3 signaling pathway and alleviate RIRIs ( 36 ); traprostalitib reduces mitochondrial damage during RIRIs in rats ( 37 ); dexmedetomidine may relieve RIRIs by suppressing the inflammatory responses ( 38 ). These drugs or molecular compounds may be potential drugs for the future treatment of RIRIs.…”

Deletion of Smooth Muscle Lethal Giant Larvae 1 Promotes Neointimal Hyperplasia in Mice

“…Also, PIAS3, known as protein inhibitor of activated STAT3, could block the DNA-binding activity of STAT3 and inhibit STAT3-mediated gene expression ( Chung et al, 1997 ). Moreover, the expression of STAT3 could be modulated by transcription factors such as PPARγ, Src and SMAD3, or microRNAs (miRNAs) such as miR-125a-5p and miR-519a ( Xiao et al, 2017 ; Li et al, 2018 ; Xu et al, 2018 ; Liu et al, 2021 ; Zhang et al, 2021 ). In addition, some small molecules such as SD-36 could degrade STAT3 to disrupt its biological function ( Bai et al, 2019 ; Zhou et al, 2019 ).…”

Effects of propofol on macrophage activation and function in diseases

“…The reason may be that propofol does not alter the anti-inflammatory or tissue repair functions of M2 macrophages ( Kochiyama et al, 2019 ). However, a recent study suggested that propofol improved renal ischemia-reperfusion injury by inducing the expression of the M2 polarization marker via the PPARγ/STAT3 pathway ( Liu et al, 2021b ). The pathways and effect of propofol on the polarization of macrophages are shown in Figure 3 .…”

“…Notably, many clinical and preclinical studies showed that propofol reduced ischemic damage to vital organs, such as the heart ( Nederlof et al, 2017 ), brain ( Sousa et al, 2021 ), kidney ( Liu et al, 2021b ), and lung ( Sousa et al, 2021 ). Propofol reduced CD45 + and increased vascular cell adhesion molecule (VCAM)-1 in the ischemic stroke model, but it did not protect the brain or lung in experimental acute ischemic stroke.…”

“…Propofol induced the infiltration of macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype in a rat model of renal ischemia-reperfusion injury (rl/R). The M1 to M2 phenotypes of macrophages were reduced after reperfusion ( Liu et al, 2021b ), which accelerated the healing of ischemic tissue and promoted the formation of new blood vessels. Propofol may also reduce rl/R-induced acute lung injury (ALI) via the up-regulation of sirtuin (STRT)-1 in the lung, and rl/R stimulation may activate focal proteins caspase-1, nucleotide oligomerization domain (NOD)-like receptor pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), IL-1β and IL-18 in the lung, but the expression of STRT1 mRNA and protein were decreased ( Liu et al, 2020 ).…”