Honokiol alleviates sepsis-induced acute kidney injury in mice by targeting the miR-218-5p/heme oxygenase-1 signaling pathway

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Abstract

Background

Honokiol is a low-molecular-weight natural product and has been reported to exhibit anti-inflammatory activity.

Objectives

Our study aimed to investigate the influence of honokiol on sepsis-induced acute kidney injury (AKI) in a mouse model.

Material and methods

A cecal ligation and puncture (CLP) surgical operation was performed to establish a sepsis-induced acute kidney injury model in mice. Renal histomorphological analysis was performed with periodic acid-Schiff (PAS) staining. The levels of inflammatory markers in serum were measured by ELISA assay. The mRNA and protein levels were assayed by RT-qPCR and western blotting, respectively. Annexin V-FITC/PI staining was used to evaluate glomerular mesangial cell (GMC) apoptosis.

Results

The results revealed that honokiol significantly increased the survival rate in mice undergoing a CLP operation. Inflammatory cytokines, such as TNF-α, IL-6 and IL-1β, were significantly inhibited in honokiol-treated septic mice compared with the CLP group. In addition, honokiol showed the ability to reverse CLP-induced AKI in septic mice. Furthermore, heme oxygenase-1 (HO-1) expression levels were significantly up-regulated and miR-218-5p was markedly down-regulated in honokiol-treated septic mice as compared to CLP-operated mice. Bioinformatics and experimental measurements showed that HO-1 was a direct target of miR-218-5p. In vitro experiments showed that both honokiol and miR-218-5p inhibitors blocked lipopolysaccharide (LPS)-induced cell growth inhibition and GMC apoptosis by increasing the expression of HO-1.

Conclusions

Honokiol ameliorated AKI in septic mice and LPS-induced GMC dysfunction, and the underlying mechanism was mediated, at least partially, through the regulation of miR-218-5p/HO-1 signaling.

Electronic supplementary material

The online version of this article (10.1186/s11658-019-0142-4) contains supplementary material, which is available to authorized users.

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Most cited references 39

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Sepsis and acute kidney injury.

Abolfazl Zarjou, Anupam Agarwal (2011)

Sepsis is a severe and dysregulated inflammatory response to infection characterized by end-organ dysfunction distant from the primary site of infection. Development of acute kidney injury (AKI) during sepsis increases patient morbidity, predicts higher mortality, has a significant effect on multiple organ functions, is associated with an increased length of stay in the intensive care unit, and hence consumes considerable healthcare resources. When compared with AKI of nonseptic origin, septic AKI is characterized by a distinct pathophysiology and therefore requires a different approach. Despite impressive advances in several fields of medicine, the pathophysiology, diagnostic procedures, and appropriate therapeutic interventions in sepsis are still highly debatable. Numerous immunomodulatory agents showing promise in preclinical studies fail to reduce the overwhelmingly high mortality rate of sepsis and provoke AKI when compared with other critically ill patients. Major impediments to progress in understanding, early diagnosis, and application of appropriate therapeutic modalities in sepsis-induced AKI include limited histopathologic information, few animal models that closely mimic human sepsis, and a relative shortage of specific diagnostic tools. Here we discuss the most recent advances in understanding the fundamental mechanisms of sepsis-induced AKI, characteristics of relevant animal models available, and potential therapies.

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Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial SIRT3

Vinodkumar B Pillai, Sadhana A. Samant, Nagalingam R Sundaresan … (2015)

Honokiol (HKL) is a natural biphenolic compound derived from the bark of magnolia trees with anti-inflammatory, anti-oxidative, anti-tumor and neuroprotective properties. Here we show that HKL blocks agonist-induced and pressure overload-mediated, cardiac hypertrophic responses, and ameliorates pre-existing cardiac hypertrophy, in mice. Our data suggest that the anti-hypertrophic effects of HKL depend on activation of the deacetylase SIRT3. We demonstrate that HKL is present in mitochondria, enhances SIRT3 expression nearly two-fold and suggest that HKL may bind to SIRT3 to further increase its activity. Increased SIRT3 activity is associated with reduced acetylation of mitochondrial SIRT3 substrates, MnSOD and OSCP. HKL-treatment increases mitochondrial rate of oxygen consumption and reduces ROS synthesis in wild-type, but not in SIRT3-KO cells. Moreover, HKL-treatment blocks cardiac fibroblast proliferation and differentiation to myofibroblasts in SIRT3-dependent manner. These results suggest that HKL is a pharmacological activator of SIRT3 capable of blocking, and even reversing, the cardiac hypertrophic response.

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Cardioprotective and antiapoptotic effects of heme oxygenase-1 in the failing heart.

J. Partridge, G Wang, Aruni Bhatnagar … (2010)

Heme oxygenase-1 (HO-1) is an inducible stress-response protein that imparts antioxidant and antiapoptotic effects. However, its pathophysiological role in cardiac remodeling and chronic heart failure (HF) is unknown. We hypothesized that induction of HO-1 in HF alleviates pathological remodeling. Adult male nontransgenic and myocyte-restricted HO-1 transgenic mice underwent either sham operation or coronary ligation to induce HF. Four weeks after ligation, nontransgenic HF mice exhibited postinfarction left ventricular (LV) remodeling and dysfunction, hypertrophy, fibrosis, oxidative stress, apoptosis, and reduced capillary density, associated with a 2-fold increase in HO-1 expression in noninfarcted myocardium. Compared with nontransgenic mice, HO-1 transgenic HF mice exhibited significantly (P<0.05) improved postinfarction survival (94% versus 57%) and less LV dilatation (end-diastolic volume, 46+/-8 versus 85+/-32 microL), mechanical dysfunction (ejection fraction, 65+/-9% versus 49+/-16%), hypertrophy (LV/tibia length 4.4+/-0.4 versus 5.2+/-0.6 mg/mm), interstitial fibrosis (11.2+/-3.1% versus 18.5+/-3.5%), and oxidative stress (3-fold reduction in tissue malondialdehyde). Moreover, myocyte-specific HO-1 overexpression in HF promoted tissue neovascularization and ameliorated myocardial p53 expression (2-fold reduction) and apoptosis. In isolated mitochondria, mitochondrial permeability transition was inhibited by HO-1 in a carbon monoxide (CO)-dependent manner and was recapitulated by the CO donor tricarbonylchloro(glycinato)ruthenium(II) (CORM-3). HO-1-derived CO also prevented H2O2-induced cardiomyocyte apoptosis and cell death. Finally, in vivo treatment with CORM-3 alleviated postinfarction LV remodeling, p53 expression, and apoptosis. HO-1 induction in the failing heart is an important cardioprotective adaptation that opposes pathological LV remodeling, and this effect is mediated, at least in part, by CO-dependent inhibition of mitochondrial permeability transition and apoptosis. Augmentation of HO-1 or its product, CO, may represent a novel therapeutic strategy for ameliorating HF.

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Author and article information

Contributors

Tao Zhang: (+86)13612013864 , zhang_taohh@163.com

Journal

Journal ID (nlm-ta): Cell Mol Biol Lett

Journal ID (iso-abbrev): Cell. Mol. Biol. Lett

Title: Cellular & Molecular Biology Letters

Publisher: BioMed Central (London )

ISSN (Print): 1425-8153

ISSN (Electronic): 1689-1392

Publication date (Electronic): 22 February 2019

Publication date PMC-release: 22 February 2019

Publication date Collection: 2019

Volume: 24

Electronic Location Identifier: 15

Affiliations

[1 ]ISNI 0000 0004 1758 2086, GRID grid.413605.5, Department of of Intensive Care Unit, , Tianjin Huanhu Hospital, ; No. 6 Jizhao Road, Tianjin, 300060 People’s Republic of China

[2 ]ISNI 0000 0004 1758 2086, GRID grid.413605.5, Department of Neurology, , Tianjin Huanhu Hospital, ; Tianjin, 300060 People’s Republic of China

Article

Publisher ID: 142

DOI: 10.1186/s11658-019-0142-4

PMC ID: 6387556

PubMed ID: 30833971

SO-VID: 3ccc9216-0869-4902-8f68-792264ad4068

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 9 November 2018

Date accepted : 13 February 2019

Custom metadata

Keywords: honokiol,sepsis,acute kidney injury,heme oxygenase-1

Data availability:

Keywords: honokiol, sepsis, acute kidney injury, heme oxygenase-1

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Honokiol alleviates sepsis-induced acute kidney injury in mice by targeting the miR-218-5p/heme oxygenase-1 signaling pathway

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Abstract

Background

Objectives

Material and methods

Results

Conclusions

Electronic supplementary material

Related collections

Karger: Nephrology

Most cited references 39

Sepsis and acute kidney injury.

Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial SIRT3

Cardioprotective and antiapoptotic effects of heme oxygenase-1 in the failing heart.

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Article

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Cited by 26

Most referenced authors 689