Mangiferin Attenuate Sepsis-Induced Acute Kidney Injury via Antioxidant and Anti-Inflammatory Effects

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Abstract

Background: Acute kidney injury (AKI) is a frequent and serious complication of sepsis. A growing body of evidence now suggests that inflammatory reactions and tubular dysfunction induced by oxidative stressinvolved in the mechanisms of the disease. This study aimed to determine the role of anti-inflammatory and anti-oxidant activities of mangiferin (MA) in sepsis-induced AKI. Methods: We investigated the effects of MA on apoptosis of rat kidney proximal tubular cell (RPTC), together with renal function and morphological alterations of mice undergoing cecal-ligation and puncture (CLP). The levels of oxidative stress in kidney tissues were also determined. Moreover, we mainly focus on the effects of MA in regulating the production of NLRP3 and Nrf2 in the present study. Results: The exposure to LPS (5 Vg/ml) yielded a signiﬁcant increase of apoptosis in RPTC cells, which was largely inhibited by MA pretreatment. MA attenuates renal dysfunction and ameliorates the morphological changes in the septic mice induced by CLP. MA inhibits oxidative stress, decreases serum levels of IL-1F and IL-18, and prevents tubular epithelial cells apoptosis in kidneys of CLP mice model. Data in this study also suggest that MA promotes Nrf2 expression and suppresses renal NLRP3 inflammasome activation. Conclusion: In summary, MA protects against sepsis-induced AKI through NLRP3 inflammasome inhibition and Nrf2 up-regulation. Thus, the mangiferin could thus be a promising candidate for development of a multi-potent drug. i 2014 S. Karger AG, Basel

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Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003.

Viktor Y Dombrovskiy, Andrew Martin, Jagadeeshan Sunderram … (2007)

To determine recent trends in rates of hospitalization, mortality, and hospital case fatality for severe sepsis in the United States. Trend analysis for the period from 1993 to 2003. U.S. community hospitals from the Nationwide Inpatient Sample that is a 20% stratified sample of all U.S. community hospitals. Subjects of any age with sepsis including severe sepsis who were hospitalized in the United States during the study period. None. Utilizing International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for septicemia and major organ dysfunction, we identified 8,403,766 patients with sepsis, including 2,857,476 patients with severe sepsis, who were hospitalized in the United States from 1993 to 2003. The percentage of severe sepsis cases among all sepsis cases increased continuously from 25.6% in 1993 to 43.8% in 2003 (p < .001). Age-adjusted rate of hospitalization for severe sepsis grew from 66.8 +/- 0.16 to 132.0 +/- 0.21 per 100,000 population (p < .001). Age-adjusted, population-based mortality rate within these years increased from 30.3 +/- 0.11 to 49.7 +/- 0.13 per 100,000 population (p < .001), whereas hospital case fatality rate fell from 45.8% +/- 0.17% to 37.8% +/- 0.10% (p < .001). During each study year, the rates of hospitalization, mortality, and case fatality increased with age. Hospitalization and mortality rates in males exceeded those in females, but case fatality rate was greater in females. From 1993 to 2003, age-adjusted rates for severe sepsis hospitalization and mortality increased annually by 8.2% (p < .001) and 5.6% (p < .001), respectively, whereas case fatality rate decreased by 1.4% (p < .001). The rate of severe sepsis hospitalization almost doubled during the 11-yr period studied and is considerably greater than has been previously predicted. Mortality from severe sepsis also increased significantly. However, case fatality rates decreased during the same study period.

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Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis.

Wenge Li, Tin Oo Khor, Changjiang Xu … (2008)

Oxidative stress has been implicated in the etiology of neurodegenerative disease, cancer and aging. Indeed, accumulation of reactive oxygen and nitrogen species generated by inflammatory cells that created oxidative stress is thought to be one of the major factor by which chronic inflammation contributes to neoplastic transformation as well as many other diseases. We have recently reported that mice lacking nuclear factor-erythroid 2-related factor 2 (Nrf2) are more susceptible to dextran sulfate sodium (DSS)-induced colitis and colorectal carcinogenesis. Nrf2 is a basic leucine zipper redox-sensitive transcriptional factor that plays a center role in ARE (antioxidant response element)-mediated induction of phase II detoxifying and antioxidant enzymes. We found that increased susceptibility of Nrf2 deficient mice to DSS-induced colitis and colorectal cancer was associated with decreased expression of antioxidant/phase II detoxifying enzymes in parallel with upregulation of pro-inflammatory cytokines/biomarkers. These findings suggest that Nrf2 may play an important role in defense against oxidative stress possibly by activation of cellular antioxidant machinery as well as suppression of pro-inflammatory signaling pathways. In addition, in vivo and in vitro data generated from our laboratory suggest that many dietary compounds can differentially regulate Nrf2-mediated antioxidant/anti-inflammatory signaling pathways as the first line defense or induce apoptosis once the cells have been damaged. In this review, we will summarize our thoughts on the potential cross-talks between Nrf2 and NFkappaB pathways. Although the mechanisms involved in the cross-talk between these signaling pathways are still illusive, targeting Nrf2-antioxidative stress signaling is an ideal strategy to prevent or treat oxidative stress-related diseases.

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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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Author and article information

Journal

Journal ID (publisher-id): AJN

Journal ID (nlm-ta): Am J Nephrol

Journal ID (doi): 10.1159/issn.0250-8095

Title: American Journal of Nephrology

Publisher: S. Karger AG

ISSN (Print): 0250-8095

ISSN (Electronic): 1421-9670

Publication date Subscription-year: 2014

Publication date (Print): December 2014

Publication date (Electronic): 22 November 2014

Volume: 40

Issue: 5

Pages: 441-450

Affiliations

Nephrology Department, 2nd Xiangya Hospital, Central South University, Key Lab of Kidney Disease and Blood Purification in Hunan, Changsha, Hunan, PR China

Author notes

*Youming Peng, Nephrology Department, 2nd Xiangya Hospital, Central South University, Key Lab of Kidney Disease and Blood Purification in Hunan, 139 Renmin Road, Changsha, Hunan 410011 (PR China), E-Mail ympeng2011@aliyun.com

Article

Publisher ID: 369220 Other ID: Am J Nephrol 2014;40:441-450

DOI: 10.1159/000369220

PubMed ID: 25427663

SO-VID: acb964c7-98db-421f-bf41-3c5bbff07f10

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 13 September 2014

Date accepted : 15 October 2014

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Figures: 5, Tables: 1, Pages: 10

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Mangiferin Attenuate Sepsis-Induced Acute Kidney Injury via Antioxidant and Anti-Inflammatory Effects

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Abstract

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Karger: Nephrology

Most cited references 29

Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003.

Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis.

Sepsis and acute kidney injury.

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Cited by 42

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