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Complement Inhibitor CRIg/FH Ameliorates Renal Ischemia Reperfusion Injury via Activation of PI3K/AKT Signaling.

ABSTRACT: Complement activation is involved in the pathogenesis of ischemia reperfusion injury (IRI), which is an inevitable process during kidney transplantation. Therefore, complement-targeted therapeutics hold great potential in protecting the allografts from IRI. We observed universal deposition of C3d and membrane attack complex in human renal allografts with delayed graft function or biopsy-proved rejection, which confirmed the involvement of complement in IRI. Using FB-, C3-, C4-, C5-, C5aR1-, C5aR2-, and C6-deficient mice, we found that all components, except C5aR2 deficiency, significantly alleviated renal IRI to varying degrees. These gene deficiencies reduced local (deposition of C3d and membrane attack complex) and systemic (serum levels of C3a and C5a) complement activation, attenuated pathological damage, suppressed apoptosis, and restored the levels of multiple local cytokines (e.g., reduced IL-1?, IL-9, and IL-12p40 and increased IL-4, IL-5, IL-10, and IL-13) in various gene-deficient mice, which resulted in the eventual recovery of renal function. In addition, we demonstrated that CRIg/FH, which is a targeted complement inhibitor for the classical and primarily alternative pathways, exerted a robust renoprotective effect that was comparable to gene deficiency using similar mechanisms. Further, we revealed that PI3K/AKT activation, predominantly in glomeruli that was remarkably inhibited by IRI, played an essential role in the CRIg/FH renoprotective effect. The specific PI3K antagonist duvelisib almost completely abrogated AKT phosphorylation, thus abolishing the renoprotective role of CRIg/FH. Our findings suggested that complement activation at multiple stages induced renal IRI, and CRIg/FH and/or PI3K/AKT agonists may hold the potential in ameliorating renal IRI.

SUBMITTER: Hu C

PROVIDER: S-EPMC6287101 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Complement Inhibitor CRIg/FH Ameliorates Renal Ischemia Reperfusion Injury via Activation of PI3K/AKT Signaling.

Hu Chao C Li Long L Ding Peipei P Li Ling L Ge Xiaowen X Zheng Long L Wang Xuanchuan X Wang Jina J Zhang Weitao W Wang Na N Gu Hongyu H Zhong Fan F Xu Ming M Rong Ruiming R Zhu Tongyu T Hu Weiguo W

Journal of immunology (Baltimore, Md. : 1950) 20181114 12

Complement activation is involved in the pathogenesis of ischemia reperfusion injury (IRI), which is an inevitable process during kidney transplantation. Therefore, complement-targeted therapeutics hold great potential in protecting the allografts from IRI. We observed universal deposition of C3d and membrane attack complex in human renal allografts with delayed graft function or biopsy-proved rejection, which confirmed the involvement of complement in IRI. Using FB-, C3-, C4</i ...[more]

PMID: 30429287

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Project description:Background: Ischemia reperfusion injury (IRI) plays a major role in solid organ transplantation. The length of warm ischemia time is critical for the extent of tissue damage in renal IRI. In this experimental study we hypothesized that local release of labile heme in renal tissue is triggered by the duration of warm ischemia (15 vs. 45 min IRI) and mediates complement activation, cytokine release, and inflammation. Methods: To induce IRI, renal pedicle clamping was performed in male C57BL/6 mice for short (15 min) or prolonged (45 min) time periods. Two and 24 h after experimental ischemia tissue injury labile heme levels in the kidney were determined with an apo-horseradish peroxidase assay. Moreover, renal injury, cytokines, and C5a and C3a receptor (C5aR, C3aR) expression were determined by histology, immunohistochemistry and qPCR, respectively. In addition, in vitro studies stimulating bone marrow-derived macrophages with LPS and the combination of LPS and heme were performed and cytokine expression was measured. Results: Inflammation and local tissue injury correlated with the duration of warm ischemia time. Labile heme concentrations in renal tissue were significantly higher after prolonged (45 min) as compared to short (15 min) IRI. Notably, expression of the inducible heme-degrading enzyme heme oxygenase-1 (HO-1) was up-regulated in kidneys after prolonged, but not after short IRI. C5aR, the pro-inflammatory cytokines IL-6 and TNF-α as well as pERK were up-regulated after prolonged, but not after short ischemia times. Consecutively, neutrophil infiltration and up-regulation of pro-fibrotic cytokines such as CTGF and PAI were more pronounced in prolonged IRI in comparison to short IRI. In vitro stimulation of macrophages with LPS revealed that IL-6 expression was enhanced in the presence of heme. Finally, administration of the heme scavenger human serum albumin (HSA) reduced the expression of pro-inflammatory cytokines, C3a receptor and improved tubular function indicated by enhanced alpha 1 microglobulin (A1M) absorption after IRI. Conclusions: Our data show that prolonged duration of warm ischemia time increased labile heme levels in the kidney, which correlates with IRI-dependent inflammation and up-regulation of anaphylatoxin receptor expression.

Project description:Ischemia-reperfusion (I/R) could cause heart irreversible damage, which is tightly combined with glucose metabolism disorder. It is demonstrated that GLUT4 (glucose transporter 4) translocation is critical for glucose metabolism in the cardiomyocytes under I/R injury. Moreover, DRD4 (dopamine receptor D4) modulate glucose metabolism, and protect neurocytes from anoxia/reoxygenation (A/R) injury. Thus, DRD4 might regulate myocardial I/R injury in association with GLUT4-mediated glucose metabolism. However, the effects and mechanisms are largely unknown. In the present study, the effect of DRD4 in heart I/R injury were studied ex vivo and in vitro. For I/R injury ex vivo, DRD4 agonist (PD168077) was perfused by Langendorff system in the isolated rat heart. DRD4 activated by PD168077 improved cardiac function in the I/R-injured heart as determined by the left ventricular developed pressure (LVDP), +dp/dt, and left ventricular end diastolic pressure (LVEDP), and reduced heart damage evidenced by infarct size, the release of troponin T (TNT) and lactate dehydrogenase (LDH). DRD4 activation diminished I/R injury induced apoptosis and enhanced cell viability impaired by I/R injury in cardiomyocyte, showed by TUNEL staining, flow cytometer and CCK8 assay. Furthermore, DRD4 activation did not change total GULT4 protein expression level but increased the membrane GULT4 localization determined by western blot. In terms of mechanism, DRD4 activation increased pPI3K/p-AKT but not the total PI3K/AKT during anoxia/reoxygenation (A/R) injury in vitro. Interestingly, PI3K inhibitor, Wortmannin, blocked PI3K/AKT pathway and depleted the membrane GULT4, and further promoted apoptosis showed by TUNEL staining, flow cytometer, western blot of cleaved caspase 3, BAX and BCL2 expression. Thus, DRD4 activation exerted a protective effect against I/R injury by promoting GLUT4 translocation depended on PI3K/AKT pathway, which enhanced the ability of glucose uptake, and ultimately reduced the apoptosis in cardiomyocytes.

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Complement Inhibitor CRIg/FH Ameliorates Renal Ischemia Reperfusion Injury via Activation of PI3K/AKT Signaling.

Publications

Complement Inhibitor CRIg/FH Ameliorates Renal Ischemia Reperfusion Injury via Activation of PI3K/AKT Signaling.

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